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Metachromatic leukodystrophy is a rare hereditary neurodegenerative disorder that causes fattysubstances to build up in cells, particularly in the brain, spinal cord and peripheral nerves. This iscaused by a deficiency of an enzyme that helps break down lipids called sulfatides. We present acase of a four-year-old boy born of non-consanguinous marriage with complaints of progressive lossof fully developed motor milestones as the inability to walk and sit (regression of achieved motormilestones). The patient was diagnosed with MLD based on whole xome sequencing and dischargedon symptomatic care and physiotherapy to improve the patient's quality of life.

Huntington’s disease (HD) is a hereditary neurodegenerative disorder of the basal ganglia for which disease-modifying treatments are not yet available. Although gene-silencing therapies are currently being tested, further molecular mechanisms must be explored to identify druggable targets for HD. Cytoplasmic polyadenylation element binding proteins 1 to 4 (CPEB1 to CPEB4) are RNA binding proteins that repress or activate translation of CPE-containing transcripts by shortening or elongating their poly(A) tail. Here, we found increased CPEB1 and decreased CPEB4 protein in the striatum of patients and mouse models with HD. This correlated with a reprogramming of polyadenylation in 17.3% of the transcriptome, markedly affecting neurodegeneration-associated genes including PSEN1, MAPT, SNCA, LRRK2, PINK1, DJ1, SOD1, TARDBP, FUS, and HTT and suggesting a new molecular mechanism in neurodegenerative disease etiology. We found decreased protein content of top deadenylated transcripts, including striatal atrophy–linked genes not previously related to HD, such as KTN1 and the easily druggable SLC19A3 (the ThTr2 thiamine transporter). Mutations in SLC19A3 cause biotin-thiamine–responsive basal ganglia disease (BTBGD), a striatal disorder that can be treated with a combination of biotin and thiamine. Similar to patients with BTBGD, patients with HD demonstrated decreased thiamine in the cerebrospinal fluid. Furthermore, patients and mice with HD showed decreased striatal concentrations of thiamine pyrophosphate (TPP), the metabolically active form of thiamine. High-dose biotin and thiamine treatment prevented TPP deficiency in HD mice and attenuated the radiological, neuropathological, and motor HD-like phenotypes, revealing an easily implementable therapy that might benefit patients with HD., This work was supported by CIBERNED-ISCIII collaborative grants 2013/09-2 to J.J.L. and 2015-2/06 and 2018/06-5 to J.J.L. and T.I., grants SAF2015-65371-R (MINECO/AEI/FEDER, UE), and grants from the Spanish Ministry of Science, Innovation and Universities (MINECO/MICINN): RTI2018-096322-B-I00 (MCIU/AEI/FEDER, UE) to J.J.L., SAF2017-88885-R (MINECO/AEI/FEDER, UE) to T.I., BFU2014-54122-P (MINECO/AEI/FEDER, UE) to R.M., and ISCIII-FEDER (PI17/00199; PI20/00625) to P.N. This work was also supported by the European Union FEDER funds, Fundación Botín–Banco Santander through its Santander Universities Global Division and Fundación Ramón Areces. A.P. and S.P. were recipients of FPI fellowships from MICINN/MINECO. A.P. was also hired through CIBERNED. J.P.-U. was contracted by SAF2017-88885-R (MINECO/AEI/FEDER, UE). D.M.-G. was supported by the “Río Hortega” programme (CM18/00142) from ISCIII-FEDER. A.E. was a recipient of Juan de la Cierva contracts from MICINN/MINECO.

Canine multiple system degeneration (CMSD) is a progressive hereditary neurodegenerative disorder commonly characterized by neuronal degeneration and loss in the cerebellum, olivary nuclei, substantia nigra, and caudate nuclei. In this article, we describe 3 cases of CMSD in Ibizan hounds. All patients exhibited marked cerebellar ataxia and had cerebellar atrophy on magnetic resonance imaging. At necropsy, all cases showed varying degrees of cerebellar atrophy, and 2 cases had gross cavitation of the caudate nuclei. Histologic findings included severe degeneration and loss of all layers of the cerebellum and neuronal loss and degeneration within the olivary nuclei, substantia nigra, and caudate nuclei. Pedigree analysis indicated an autosomal recessive mode of inheritance, but the causative gene in this breed is yet to be identified. CMSD resembles human multiple system atrophy and warrants further investigation.

Huntington’s disease (HD) is a rare hereditary neurodegenerative disorder characterized by multiple metabolic dysfunctions including defects in mitochondrial homeostasis and functions. Although we have recently reported age-related changes in the respiratory capacities in different brain areas in HD mice, the precise mechanisms of how mitochondria become compromised in HD are still poorly understood. In this study, we investigated mRNA and protein levels of selected subunits of electron transport system (ETS) complexes and ATP-synthase in the cortex and striatum of symptomatic R6/2 mice. Our findings reveal a brain-region-specific differential expression of both nuclear and mitochondrial-encoded ETS components, indicating defects of transcription, translation and/or mitochondrial import of mitochondrial ETS components in R6/2 mouse brains.

Huntington's disease (HD) is a fatal hereditary neurodegenerative disorder, best known for its clinical triad of progressive motor impairment, cognitive deficits and psychiatric disturbances, is caused by CAG-repeat expansion in exon 1 of Huntingtin (HTT). However, in addition to the neurological disease, mutant HTT (mHTT), which is ubiquitously expressed in all tissues, impairs other organ systems. Not surprisingly, cardiovascular dysautonomia as well as the deterioration of circadian rhythms are among the earliest detectable pathophysiological changes in individuals with HD. Mitochondrial dysfunction in the brain and skeletal muscle in HD has been well documented, as the disease progresses. However, not much is known about mitochondrial abnormalities in the heart. In this study, we describe a role for Drp1/Fis1-mediated excessive mitochondrial fission and dysfunction, associated with lysosomal dysfunction in H9C2 expressing long polyglutamine repeat (Q73) and in human iPSC-derived cardiomyocytes transfected with Q77. Expression of long polyglutamine repeat led to reduced ATP production and mitochondrial fragmentation. We observed an increased accumulation of damaged mitochondria in the lysosome that was coupled with lysosomal dysfunction. Importantly, reducing Drp1/Fis1-mediated mitochondrial damage significantly improved mitochondrial function and cell survival. Finally, reducing Fis1-mediated Drp1 recruitment to the mitochondria, using the selective inhibitor of this interaction, P110, improved mitochondrial structure in the cardiac tissue of R6/2 mice. We suggest that drugs focusing on the central nervous system will not address mitochondrial function across all organs, and therefore will not be a sufficient strategy to treat or slow down HD disease progression.

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expansion of a CAG repeat in the huntingtin (htt) gene, which results in an aberrant form of the protein (mhtt). This leads to motor and cognitive deficits associated with corticostriatal and hippocampal alterations. The levels of STriatal-Enriched protein tyrosine Phosphatase (STEP), a neural-specific tyrosine phosphatase that opposes the development of synaptic strengthening, are decreased in the striatum of HD patients and also in R6/1 mice, thereby contributing to the resistance to excitotoxicity described in this HD mouse model. Here, we aimed to analyze whether STEP inactivation plays a role in the pathophysiology of HD by investigating its effect on motor and cognitive impairment in the R6/1 mouse model of HD. We found that genetic deletion of STEP delayed the onset of motor dysfunction and prevented the appearance of cognitive deficits in R6/1 mice. This phenotype was accompanied by an increase in pERK1/2 levels, a delay in the decrease of striatal DARPP-32 levels and a reduction in the size of mhtt aggregates, both in the striatum and CA1 hippocampal region. We also found that acute pharmacological inhibition of STEP with TC-2153 improved cognitive function in R6/1 mice. In conclusion, our results show that deletion of STEP has a beneficial effect on motor coordination and cognition in a mouse model of HD suggesting that STEP inhibition could be a good therapeutic strategy in HD patients.

Mutations in the coding sequence of human TECPR2 were recently linked to spastic paraplegia type 49 (SPG49), a hereditary neurodegenerative disorder involving intellectual disability, autonomic-sensory neuropathy, chronic respiratory disease and decreased pain sensitivity. Here, we report the generation of a novel CRISPR-Cas9 tecpr2 knockout (tecpr2(−/−)) mouse that exhibits behavioral pathologies observed in SPG49 patients. tecpr2(−/−) mice develop neurodegenerative patterns in an age-dependent manner, manifested predominantly as neuroaxonal dystrophy in the gracile (GrN) and cuneate nuclei (CuN) of the medulla oblongata in the brainstem and dorsal white matter column of the spinal cord. Age-dependent correlation with accumulation of autophagosomes suggests compromised targeting to lysosome. Taken together, our findings establish the tecpr2 knockout mouse as a potential model for SPG49 and ascribe a new role to TECPR2 in macroautophagy/autophagy-related neurodegenerative disorders.

In light of our aging population, neurodegenerative disorders are becoming a tremendous challenge, that modern societies have to face. They represent incurable, progressive conditions with diverse and complex pathological features, followed by catastrophic occurrences of massive neuronal loss at the later stages of the diseases. Some of these disorders, like Huntington’s disease (HD), rely on defined genetic factors. HD, as an incurable, fatal hereditary neurodegenerative disorder characterized by its mid-life onset, is caused by the expansion of CAG trinucleotide repeats coding for glutamine (Q) in exon 1 of the huntingtin gene. Apart from the genetic defect, environmental factors are thought to influence the risk, onset and progression of HD. As epigenetic mechanisms are known to readily respond to environmental stimuli, they are proposed to play a key role in HD pathogenesis. Indeed, dynamic epigenomic remodeling is observed in HD patients and in brains of HD animal models. Epigenetic signatures, such as DNA methylation, histone variants and modifications, are known to influence gene expression and to orchestrate various aspects of neuronal physiology. Hence, deciphering their implication in HD pathogenesis might open up new paths for novel therapeutic concepts, which are discussed in this review.

CLN2 neuronal ceroid lipofuscinosis is a hereditary neurodegenerative disorder characterized by progressive vision loss, neurological decline, and seizures. CLN2 disease results from mutations in TPP1 that encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Children with CLN2 neuronal ceroid lipofuscinosis experience ocular disease, characterized by progressive retinal degeneration associated with impaired retinal function and gradual vision loss culminating in total blindness. A similar progressive loss of retinal function is also observed in a dog CLN2 model with a TPP1 null mutation. A study was conducted to evaluate the efficacy of periodic intravitreal injections of recombinant human (rh) TPP1 in inhibiting retinal degeneration and preserving retinal function in the canine model. TPP1 null dogs received periodic intravitreal injections of rhTPP1 in one eye and vehicle in the other eye beginning at approximately 12 weeks of age. Ophthalmic exams, in vivo ocular imaging, and electroretinography (ERG) were repeated regularly to monitor retinal structure and function. Retinal histology was evaluated in eyes collected from these dogs when they were euthanized at end-stage neurological disease (43-46 weeks of age). Intravitreal rhTPP1 dosing prevented disease-related declines in ERG amplitudes in the TPP1-treated eyes. At end-stage neurologic disease, TPP1-treated eyes retained normal morphology while the contralateral vehicle-treated eyes exhibited loss of inner retinal neurons and photoreceptor disorganization typical of CLN2 disease. The treatment also prevented the development of disease-related focal retinal detachments observed in the control eyes. Uveitis occurred secondary to the administration of the rhTPP1 but did not hinder the therapeutic benefits. These findings demonstrate that periodic intravitreal injection of rhTPP1 preserves retinal structure and function in canine CLN2 disease.

Huntington’s disease (HD) is a hereditary neurodegenerative disorder that typically manifests in midlife with motor, cognitive, and/or psychiatric symptoms. The disease is caused by a CAG triplet expansion in exon 1 of the huntingtin gene and leads to a severe neurodegeneration in the striatum and cortex. Classical electrophysiological studies in genetic HD mouse models provided important insights into the disbalance of excitatory, inhibitory and neuromodulatory inputs, as well as progressive disconnection between the cortex and striatum. However, the involvement of local cortical and striatal microcircuits still remains largely unexplored. Here we review the progress in understanding HD-related impairments in the cortical and basal ganglia circuits, and outline new opportunities that have opened with the development of modern circuit analysis methods. In particular, in vivo imaging studies in mouse HD models have demonstrated early structural and functional disturbances within the cortical network, and optogenetic manipulations of striatal cell types have started uncovering the causal roles of certain neuronal populations in disease pathogenesis. In addition, the important contribution of astrocytes to HD-related circuit defects has recently been recognized. In parallel, unbiased systems biology studies are providing insights into the possible molecular underpinnings of these functional defects at the level of synaptic signaling and neurotransmitter metabolism. With these approaches, we can now reach a deeper understanding of circuit-based HD mechanisms, which will be crucial for the development of effective and targeted therapeutic strategies.

Despite advances in understanding the pathophysiology of Huntington’s disease (HD), there are currently no effective pharmacological agents available to treat core symptoms or to stop or prevent the progression of this hereditary neurodegenerative disorder. Pridopidine, a novel small molecule compound, has demonstrated potential for both symptomatic treatment and disease modifying effects in HD. While pridopidine failed to achieve its primary efficacy outcomes (Modified motor score) in two trials (MermaiHD and HART) there were consistent effects on secondary outcomes (TMS). In the most recent study (PrideHD) pridiopidine did not differ from placebo on TMS, possibly due to a large enduring placebo effect. This review describes the process, based on in vivo systems response profiling, by which pridopidine was discovered and discusses its pharmacological profile, aiming to provide a model for the system-level effects, and a rationale for the use of pridopidine in patients affected by HD. Considering the effects on brain neurochemistry, gene expression and behaviour in vivo, pridopidine displays a unique effect profile. A hallmark feature in the behavioural pharmacology of pridopidine is its state-dependent inhibition or activation of dopamine-dependent psychomotor functions. Such effects are paralleled by strengthening of synaptic connectivity in cortico-striatal pathways suggesting pridopidine has potential to modify phenotypic expression as well as progression of HD. The preclinical pharmacological profile is discussed with respect to the clinical results for pridopidine, and proposals are made for further investigation, including preclinical and clinical studies addressing disease progression and effects at different stages of HD.

Huntington's disease (HD) is a hereditary neurodegenerative disorder of typically middle-aged onset for which there is no disease-modifying treatment. Caudate and putamen medium-sized spiny projection neurons (SPNs) most severely degenerate in HD. However, it is unclear why mutant huntingtin protein (mHTT) is preferentially toxic to these neurons or why symptoms manifest only relatively late in life. mHTT interacts with numerous neuronal proteins. Likewise, multiple SPN cellular processes have been described as altered in various HD models. Among these, altered neuronal Ca2+ influx and intracellular Ca2+ handling feature prominently and are addressed here. Specifically, we focus on extrasynaptic NMDA-type glutamate receptors, endoplasmic reticulum IP3 receptors, and mitochondria. As mHTT is expressed throughout development, compensatory processes will likely be mounted to mitigate any deleterious effects. Although some compensations can lessen mHTT's disruptive effects, others-such as upregulation of the ER-refilling store-operated Ca2+ channel response-contribute to pathogenesis. A causation-based approach is therefore necessary to decipher the complex sequence of events linking mHTT to neurodegeneration, and to design rational therapeutic interventions. With this in mind, we highlight evidence, or lack thereof, that the above alterations in Ca2+ handling occur early in the disease process, clearly interact with mHTT, and show disease-modifying potential when reversed in animals.

Pantothenate kinase-associated neurodegeneration is a rare hereditary neurodegenerative disorder associated with nucleotide variation(s) in mitochondrial human Pantothenate kinase 2 (hPanK2) protein encoding PANK2 gene, and is characterized by symptoms of extra-pyramidal dysfunction and accumulation of non-heme iron predominantly in the basal ganglia of the brain. In this study, we describe a familial case of PKAN from the State of Jammu and Kashmir (J&K), India based on the clinical findings and genetic screening of two affected siblings born to consanguineous normal parents. The patients present with early-onset, progressive extrapyramidal dysfunction, and brain Magnetic Resonance imaging (MRI) suggestive of symmetrical iron deposition in the globus pallidi. Screening the PANK2 gene in the patients as well as their unaffected family members revealed a functional single nucleotide variation, perfectly segregating in the patient’s family in an autosomal recessive mode of inheritance. We also provide the results of in-silico analyses, predicting the functional consequence of the identified PANK2 variant.

Background Progressive subcortical changes are known to occur in Huntington's disease (HD), a hereditary neurodegenerative disorder. Less is known about the occurrence and cohesion of whole brain grey matter changes in HD. Objectives We aimed to detect network integrity changes in grey matter structural covariance networks and examined relationships with clinical assessments. Methods Structural magnetic resonance imaging data of premanifest HD (n = 30), HD patients (n = 30) and controls (n = 30) was used to identify ten structural covariance networks based on a novel technique using the co-variation of grey matter with independent component analysis in FSL. Group differences were studied controlling for age and gender. To explore whether our approach is effective in examining grey matter changes, regional voxel-based analysis was additionally performed. Results Premanifest HD and HD patients showed decreased network integrity in two networks compared to controls. One network included the caudate nucleus, precuneous and anterior cingulate cortex (in HD p, Highlights • Identification of anatomical networks in Huntington's disease (HD). • Independent component analysis was used to examine structural covariance networks. • HD patients showed changes in subcortical and cortical covariance networks. • A network-based approach is sensitive to reveal early grey matter changes.

Huntington's disease (HD) is an incurable, autosomal dominant, hereditary neurodegenerative disorder that typically manifests itself in midlife. This pathology is linked to the deregulation of multiple, as yet unknown, cellular processes starting before HD onset. A human iPS cell line was generated from skin fibroblasts of a subject at the presymptomatic life stage, carrying a polyglutamine expansion in HTT gene codifying Huntingtin protein. The iPSC line contained the expected CAG expansion, expressed the expected pluripotency markers, displayed in vivo differentiation potential to the three germ layers and had a normal karyotype.

Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1) work in concert with Ugo1, for which no human equivalent has been identified thus far. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.

Alexander disease (AxD) is a rare hereditary neurodegenerative disorder caused by glial fibrillary acidic protein (GFAP) gene mutations, most of which are missense mutations. We present an AxD case with a novel de novo three-base duplication mutation in GFAP resulting in E243dup.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a hereditary neurodegenerative disorder caused by a mutation on the X chromosome. The major signs and symptoms are tremor, ataxia and parkinsonism. Up to one in 2 000 persons over 50 years of age will develop the syndrome. There is reason to believe that too few individuals in Norway undergo testing for this condition.

Using a canine model of classical late-infantile neuronal ceroid lipofuscinosis (CLN2 disease), a study was conducted to evaluate the potential pharmacological activity of recombinant human tripeptidyl peptidase-1 (rhTPP1) enzyme replacement therapy administered directly to the cerebrospinal fluid (CSF). CLN2 disease is a hereditary neurodegenerative disorder resulting from mutations in CLN2, which encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Infants with mutations in both CLN2 alleles develop normally but in the late-infantile/early-childhood period undergo progressive neurological decline accompanied by pronounced brain atrophy. The disorder, a form of Batten disease, is uniformly fatal, with clinical signs starting between 2 and 4 years of age and death usually occurring by the early teenage years. Dachshunds homozygous for a null mutation in the canine ortholog of CLN2 (TPP1) exhibit a similar disorder that progresses to end stage at 10.5–11 months of age. Administration of rhTPP1 via infusion into the CSF every other week, starting at approximately 2.5 months of age, resulted in dose-dependent significant delays in disease progression, as measured by delayed onset of neurologic deficits, improved performance on a cognitive function test, reduced brain atrophy, and increased life span. Based on these findings, a clinical study evaluating the potential therapeutic value of rhTPP1 administration into the CSF of children with CLN2 disease has been initiated.

Spinocerebellar ataxia type 2 (SCA2) is a hereditary neurodegenerative disorder caused by the expansion of the trinucleotide CAG repeats encoding elongated polyglutamine tract in ataxin-2, the SCA2 gene product. Polyglutamine diseases comprise nine genetic entities, including seven different forms of spinocerebellar ataxias, Huntington's disease, and spinal and bulbar muscular atrophy. These are pathologically characterized by neuronal loss and intranuclear aggregates or inclusions of mutant proteins including expanded polyglutamine in selected neuronal groups. Previously, we examined immunolocalization of ubiquitin, expanded polyglutamine (probed by 1C2 antibody), and ataxin-2 in genetically confirmed SCA2 patients. In the present study, we expanded this approach by distinguishing different patterns of subcellular 1C2 immunoreactivity ("granular cytoplasmic," "cytoplasmic and nuclear" and "nuclear with inclusions.") and by quantifying their regional frequencies in three autopsied SCA2 brains at different stage of the disease. Comparison with neuronal loss and gliosis revealed that overall 1C2 immunoreactivity was paralleled with their severity. Furthermore, appearance of granular cytoplasmic pattern corresponded to early stage, cytoplasmic and nuclear pattern to active stage, and nuclear with inclusions pattern to final stage. We conclude that this 1C2-immunoreactive typing may be useful for evaluating the overall severity and extent of affected regions and estimating the neuropathological stage of SCA2.

Inclusions of intermediate filaments are found in a number of neurodegenerative diseases. Using whole exome sequencing, linkage analysis and proteomics, Wong and Chiu et al. identify a new familial neurodegenerative disease with intermediate filament inclusions, linked to a mutation in the gene encoding the PKA type I-beta regulatory subunit, PRKAR1B.Pathological accumulation of intermediate filaments can be observed in neurodegenerative disorders, such as Alzheimer's disease, frontotemporal dementia and Parkinson's disease, and is also characteristic of neuronal intermediate filament inclusion disease. Intermediate filaments type IV include three neurofilament proteins (light, medium and heavy molecular weight neurofilament subunits) and alpha-internexin. The phosphorylation of intermediate filament proteins contributes to axonal growth, and is regulated by protein kinase A. Here we describe a family with a novel late-onset neurodegenerative disorder presenting with dementia and/or parkinsonism in 12 affected individuals. The disorder is characterized by a unique neuropathological phenotype displaying abundant neuronal inclusions by haematoxylin and eosin staining throughout the brain with immunoreactivity for intermediate filaments. Combining linkage analysis, exome sequencing and proteomics analysis, we identified a heterozygous c.149T > G (p.Leu50Arg) missense mutation in the gene encoding the protein kinase A type I-beta regulatory subunit (PRKAR1B). The pathogenicity of the mutation is supported by segregation in the family, absence in variant databases, and the specific accumulation of PRKAR1B in the inclusions in our cases associated with a specific biochemical pattern of PRKAR1B. Screening of PRKAR1B in 138 patients with Parkinson's disease and 56 patients with frontotemporal dementia did not identify additional novel pathogenic mutations. Our findings link a pathogenic PRKAR1B mutation to a novel hereditary neurodegenerative disorder and suggest an altered protein kinase A function through a reduced binding of the regulatory subunit to the A-kinase anchoring protein and the catalytic subunit of protein kinase A, which might result in subcellular dislocalization of the catalytic subunit and hyperphosphorylation of intermediate filaments.

Huntington's disease (HD) is a hereditary neurodegenerative disorder which is associated with severe disturbances of motor function, especially choreatic movements, cognitive decline and psychiatric symptoms. Various brain stimulation methods have been used to study brain function in patients with HD. Moreover, brain stimulation has evolved as an alternative or additive treatment option, besides current symptomatic medical treatment. This article summarizes the results of brain stimulation to better understand the characteristics of cortical excitability and plasticity in HD and gives a perspective on the therapeutic role for noninvasive and invasive neuromodulatory brain stimulation methods.

Background Huntington’s disease (HD) is an incurable hereditary neurodegenerative disorder, which manifests itself as a loss of GABAergic medium spiny (GABA MS) neurons in the striatum and caused by an expansion of the CAG repeat in exon 1 of the huntingtin gene. There is no cure for HD, existing pharmaceutical can only relieve its symptoms. Results Here, induced pluripotent stem cells were established from patients with low CAG repeat expansion in the huntingtin gene, and were then efficiently differentiated into GABA MS-like neurons (GMSLNs) under defined culture conditions. The generated HD GMSLNs recapitulated disease pathology in vitro, as evidenced by mutant huntingtin protein aggregation, increased number of lysosomes/autophagosomes, nuclear indentations, and enhanced neuronal death during cell aging. Moreover, store-operated channel (SOC) currents were detected in the differentiated neurons, and enhanced calcium entry was reproducibly demonstrated in all HD GMSLNs genotypes. Additionally, the quinazoline derivative, EVP4593, reduced the number of lysosomes/autophagosomes and SOC currents in HD GMSLNs and exerted neuroprotective effects during cell aging. Conclusions Our data is the first to demonstrate the direct link of nuclear morphology and SOC calcium deregulation to mutant huntingtin protein expression in iPSCs-derived neurons with disease-mimetic hallmarks, providing a valuable tool for identification of candidate anti-HD drugs. Our experiments demonstrated that EVP4593 may be a promising anti-HD drug. Electronic supplementary material The online version of this article (doi:10.1186/s13024-016-0092-5) contains supplementary material, which is available to authorized users.

Chahwan C, Chahwan R. Aicardi–Goutieres syndrome: from patients to genes and beyond. Aicardi–Goutieres syndrome (AGS) is a hereditary neurodegenerative disorder characterized mainly by early onset progressive encephalopathy, concomitant with an increase in interferon-α levels in the cerebrospinal fluid. Although it was initially mistaken for intrauterine viral infections, AGS has now been genetically attributed to a lack of adequate processing of cellular nucleic acid debris, which culminates in the perpetual trigger of the innate and acquired immune responses. Although the exact mechanisms governing AGS are not fully understood, significant strides have been recently achieved in better characterizing the disorder and the molecular functions of the five known proteins found mutated in AGS. Studies have now uncovered that AGS is tightly linked with the predisposition to other autoimmune disorders such as familial chilblain lupus and systemic lupus erythematosus. Moreover, at least two of the proteins mutated in AGS, namely TREX1 and SAMHD1, also seem to have antagonistic roles in safeguarding humans from human immunodeficiency virus (HIV) infections. We hereby synthesize the current developments into the greater framework of AGS and suggest that a better understanding of AGS might help usher a better treatment not only for some autoimmune disorders but also possibly for patients suffering from HIV infections, too.

Skeletal muscle loss and dysfunction in aging and chronic diseases is one of the major causes of mortality in patients, and is relevant for a wide variety of diseases such as neurodegeneration and cancer. Muscle loss is accompanied by changes in gene expression and metabolism that lead to contractile impairment and likely affect whole‐body metabolism and function. The changes may be caused by inactivity, inflammation, age‐related factors or unbalanced nutrition. Although links with skeletal muscle loss have been found in diseases with disparate aetiologies, for example both in Huntington's disease (HD) and cancer cachexia, the outcome is a similar impairment and mortality. This short commentary aims to summarize recent achievements in the identification of common mechanisms leading to the skeletal muscle wasting syndrome seen in diseases as different as cancer and HD. The latter is the most common hereditary neurodegenerative disorder and muscle wasting is an important component of its pathology. In addition, possible therapeutic strategies for anti‐cachectic treatment will be also discussed in the light of their translation into possible therapeutic approaches for HD.

Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by an unstable expansion of cytosine-adenine-guanine (CAG) repeats in the HD gene. The symptoms include cognitive dysfunction and severe motor impairment with loss of voluntary movement coordination that is later replaced by bradykinesia and rigidity. The neuropathology is characterized by neuronal loss mainly in the striatum and cortex, and the appearance of neuronal intranuclear inclusions of mutant huntingtin. The mechanisms responsible for neurodegeneration are still not fully understood although excitotoxicity and a consequent increase in intracellular calcium concentration as well as the activation of caspases and calapins are known to play a key role. There is currently no satisfactory treatment or cure for this disease. The YAC128 transgenic mice express the full-length human HD gene with 128 CAG repeats and constitute a unique model for the study of HD as they replicate the slow and biphasic progression of behavioral deficits characteristic of the human condition and show striatal neuronal loss. As such, these transgenic mice have been an invaluable model not only for the elucidation of the neurodegenerative pathways in HD, but also for the screening and development of new therapeutic approaches. Here, I will review the unique characteristics of this transgenic HD model and will provide a summary of the therapies that have been tested in these mice, namely: potentiation of the protective roles of wild-type huntingtin and mutant huntingtin aggregation, transglutaminase inhibition, inhibition of glutamate- and dopamine-induced toxicity, apoptosis inhibition, use of essential fatty acids, and the novel approach of intrabody gene therapy. The insights obtained from these and future studies will help identify potential candidates for clinical trials and will ultimately contribute to the discovery of a successful treatment for this devastating neurodegenerative disorder.

Dentatorubral-pallidoluysian atrophy (DRPLA) is a dominant hereditary neurodegenerative disorder caused by the expansion of a poly-glutamine (poly-Q) repeat in Atrophin-1 protein. Ectopic expression of a poly-Q expanded human Atrophin-1 is sufficient to induce DRPLA phenotypes in mice. However, it is still unclear whether the dominant effect of poly-Q expansion is due to the functional interference with wild-type Atrophin-1 proteins, which exist in both patients and transgenic mice. Here we report the generation and analysis of an Atrophin-1 targeting allele that expresses a truncated protein lacking both the poly-Q repeat and following C-terminal peptides. Homozygous mutants exhibit growth retardation and progressive male infertility, but no obvious signs of neurodegeneration. Moreover, the mutant allele neither blocked nor enhanced the neurodegenerative phenotypes caused by a poly-Q expanded transgene. These results support the model that poly-Q expanded Atrophin-1 proteins cause DRPLA in a manner independent of any functional interaction with wild-type Atrophin-1 proteins.

Huntington’s Disease (HD) is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. We have created an HD mouse model that resolves the effects of the inherited and somatic expansions. We show here that suppressing somatic expansion substantially delays the onset of disease in littermates that inherit the same disease-length allele. Furthermore, a pharmacological inhibitor, XJB-5-131, inhibits the lengthening of the repeat tracks, and correlates with rescue of motor decline in these animals. The results provide evidence that pharmacological approaches to offset disease progression are possible., Author Summary Huntington’s Disease (HD) is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. There is no correction for the inherited mutation, but if somatic expansion contributes to disease, then a therapeutic approach is possible. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. Here we describe a mouse model of Huntington’s disease that allows us to separate out the effects of the inherited gene from the expansion that occurs during life. We find that blocking the continued expansion of the gene causes a delay in onset of symptoms. This result opens the doors to future therapeutics designed to shorten the repeat.

© The Author 2015. Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by brain atrophy particularly in striatum leading to personality changes, chorea and dementia. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase in the crossroad of many signaling pathways that is highly pleiotropic as it phosphorylates more than hundred substrates including structural, metabolic, and signaling proteins. Increased GSK-3 activity is believed to contribute to the pathogenesis of neurodegenerative diseases like Alzheimer's disease and GSK-3 inhibitors have been postulated as therapeutic agents for neurodegeneration. Regarding HD, GSK-3 inhibitors have shown beneficial effects in cell and invertebrate animal models but no evident efficacy in mouse models. Intriguingly, those studies were performed without interrogating GSK-3 level and activity in HD brain. Herewe aim to explore the level and also the enzymatic activity of GSK-3 in the striatum and other less affected brain regions of HD patients and of the R6/1 mouse model to then elucidate the possible contribution of its alteration to HD pathogenesis by genetic manipulation in mice.We report a dramatic decrease in GSK-3 levels and activity in striatum and cortex of HD patients with similar results in the mouse model. Correction of the GSK-3 deficit inHDmice, by combining with transgenic mice with conditional GSK-3 expression, resulted in amelioration of their brain atrophy and behavioral motor and learning deficits. Thus, our results demonstrate that decreased brain GSK-3 contributes to HD neurological phenotype and open new therapeutic opportunities based on increasing GSK-3 activity or attenuating the harmful consequences of its decrease., This work was supported by Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CiberNed-Instituto de salud Carlos III) and by grants from Ministerio de Ciencia (MEC, MICINN, MINECO), Comunidad Autónoma de Madrid and Fundación Ramón Areces. A.M.

Huntington's disease (HD) is a hereditary neurodegenerative disorder. The genetic cause is an expansion of CAG repeats located in the IT15 gene. Though the number of CAG repeats ((CAG)n) can largely explain the age at onset (AAO) of symptoms, a percentage of its variation could be attributed to modifier genes and to environmental factors. The study aimed to evaluate the influence of genetic modifiers of the AAO of HD including: (CAG)n and del2642 in the IT15 gene, ADORA2A rs5751876, HAP1 rs4523977, PGC1-α rs7665116 and UCH-L1 rs5030732. Eighteen patients with positive family history and HD-suggestive symptoms were recruited. The (CAG)n and gene polymorphisms were determined by different molecular biology techniques. We observed that the (CAG)n influenced in a 64.5% of the variability in the AAO. We also showed that the rs5751876 variant significantly affected this variability. However, the influence of UCH-L1, del2642, HAP1 and PGC1-α gene polymorphisms could not be replicated, perhaps due to small sample size. Genetic studies including the molecular determination of (CAG)n, in addition to other genetic modifiers involved in the variability of the AAO, were first performed in Uruguay. We could replicate in our cohort the anticipation effect on the AAO by the ADORA2A rs5751876. Our results confirm the usefulness of an expanded molecular characterization in HD patients.

Background Spinocerebellar Ataxia Type 3/Machado-Joseph Disease (SCA3/MJD) is a hereditary neurodegenerative disorder resulting from the expansion of CAG repeats in the ATXN3 gene. It is the most common autosomal dominant ataxia in the world, but its frequency prevalence in Cuba remains uncertain. We undertook a national study in order to characterize the ATXN3 gene and to determine the prevalence of SCA3/MJD in Cuba. Results Twenty-two individuals belonging to 8 non-related families were identified as carriers of an expanded ATXN3 allele. The affected families come from the central and western region of the country. Ataxia of gait was the initial symptom in all of the cases. The normal alleles ranged between 14 and 33 CAG repeats while the expanded ones ranged from 63 to 77 repeats. The mean age at onset was 40 ± 9 years and significantly correlated with the number of CAG repeats in the expanded alleles. Conclusions This disorder was identified as the second most common form of spinocerebellar ataxia (SCA) in Cuba based on molecular testing, and showing a different geographical distribution from that of SCA2. This research constitutes the first clinical and molecular characterization of Cuban SCA3 families, opening the way for the implementation of predictive diagnosis for at risk family members.

Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by motor, cognitive and behavioural abnormalities. HD is caused by a mutation in the huntingtin gene which produces an enlarged chain of CAG triplets in this gene and an expanded chain of poliglutamines in the N terminal portion of the protein. HD is characterized by neuronal loss and atrophy of several brain nuclei, preferentially in the striatum.

Huntington's disease (HD) is a hereditary neurodegenerative disorder that gradually robs sufferers of the ability to control movements and induces psychological and cognitive impairments. This devastating, lethal disease is one of several neurological disorders caused by trinucleotide expansions in affected genes, including spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and spinal bulbar muscular atrophy. HD symptoms are associated with region-specific neuronal loss within the central nervous system, but to date the mechanism of this selective cell death remains unknown. Strong evidence from studies in humans and animal models suggests the involvement of energy metabolism defects, which may contribute to excitotoxic processes, oxidative dmage, and altered gene regulation. The development of transgenic mouse models expressing the human HD mutation has provided novel opportunities to explore events underlying selective neuronal death in HD, which has hitherto been impossible in humans. Here we discuss how animal models are redefining the role of energy metabolism in HD etiology.

Spinal muscular atrophy (SMA) type I is an autosomal recessive disorder characterized by loss of lower motor neurons in the spinal cord. This severe hereditary neurodegenerative disorder is an important cause of morbidity in the neonate and the leading hereditary cause of infant mortality. The characteristic degeneration of anterior horn cells in the spinal cord leads to progressive muscular weakness and atrophy of the skeletal muscles. In SMA type I, the most severe form of SMA, death usually ensues by 2 years of age from respiratory failure or infection. Accurate diagnosis is now available through genetic testing, and progress is being made toward the development of therapy based on understanding of the disease mechanism. The neonatal nurse plays a pivotal role in identifying and caring for these medically fragile infants and in providing support and education for parents and families.

Huntington's disease (HD) is a devastating hereditary neurodegenerative disorder, the progression of which cannot be prevented by any neuroprotective approach, despite major advances in the understanding of its pathogenesis. The study of several animal models of the disease has led to the discovery of both loss-of-normal and gain-of-toxic functions of the mutated huntingtin protein and the elucidation of the mechanisms that underlie the formation of huntingtin aggregates and nuclear inclusions. Moreover, these models also provide good evidence of a role for excitotoxicity and mitochondrial metabolic impairments in striatal neuronal death. Adenosine has neuroprotective potential in both acute and chronic neurological disorders such as stroke or Parkinson's disease. Here we review experimental data on the role of A1 and A2A adenosine receptors in HD that warrant further investigation of the beneficial effects of A1 agonists and A2A antagonists in animal models of HD. Future pharmacological analysis of adenosine receptors could justify the use of A1 agonists and A2A antagonists for the treatment of HDin clinical trials.

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by the expansion of a polyglutamine stretch within the huntingtin protein (HTT). The neurological symptoms, that involve motor, cognitive and psychiatric disturbances, are caused by neurodegeneration that is particularly widespread in the basal ganglia and cereberal cortex. HTT is ubiquitously expressed and in recent years it has become apparent that HD patients experience a wide array of peripheral organ dysfunction including severe metabolic phenotype, weight loss, HD-related cardiomyopathy and skeletal muscle wasting. Although skeletal muscles pathology became a hallmark of HD, the mechanisms underlying muscular atrophy in this disorder are unknown. Skeletal muscles account for approximately 40% of body mass and are highly adaptive to physiological and pathological conditions that may result in muscle hypertrophy (due to increased mechanical load) or atrophy (inactivity, chronic disease states). The atrophy is caused by degeneration of myofibers and their replacement by fibrotic tissue is the major pathological feature in many genetic muscle disorders. Under normal physiological conditions the muscle function is orchestrated by a network of intrinsic hypertrophic and atrophic signals linked to the functional properties of the motor units that are likely to be imbalanced in HD. In this article, we highlight the emerging field of research with particular focus on the recent studies of the skeletal muscle pathology and the identification of new disease-modifying treatments.

Introduction: Huntington's disease (HD) is the most common hereditary neurodegenerative disorder. Despite the fact that both the gene and the mutation causing this monogenetic disorder were identified more than 20 years ago, disease-modifying therapies for HD have not yet been established. Review: While intense preclinical research and large cohort studies in HD have laid foundations for tangible improvements in understanding HD and caring for HD patients, identifying targets for therapeutic interventions and developing novel therapeutic modalities (new chemical entities and advanced therapies using DNA and RNA molecules as therapeutic agents) continues to be an ongoing process. The authors review recent achievements in HD research and focus on approaches towards disease-modifying therapies, ranging from huntingtin-lowering strategies to improving huntingtin clearance that may be promoted by posttranslational HTT modifications. Conclusion: The nature and number of upcoming clinical studies/trials in HD is a reason for hope for HD patients and their families.

Of the neurodegenerative diseases presented in this book, Huntington’s disease (HD) stands as the archetypal autosomal dominantly inherited neurodegenerative disorder. Its occurrence through generations of affected families was noted long before the basic genetic underpinnings of hereditary diseases was understood. The early classification of HD as a distinct hereditary neurodegenerative disorder allowed the study of this disease to lead the way in the development of our understanding of the mechanisms of human genetic disorders. Following its clinical and pathologic characterization, the causative genetic mutation in HD was subsequently identified as a trinucleotide (CAG) repeat expansion in the huntingtin (HTT) gene, and consequently, the HTT gene and huntingtin protein have been studied in great detail. Despite this concentrated effort, there is still much about the function of huntingtin that still remains unknown. Presented in this chapter is an overview of the current knowledge on the normal function of huntingtin and some of the potential neurobiologic mechanisms by which the mutant HTT gene may mediate neurodegeneration in HD.

Autosomal recessive juvenile parkinsonism is a hereditary neurodegenerative disorder, usually beginning before the age of 40. We found three exonic deletions and two novel point mutations (Arg33Stop and Cys431Phe) in six families with autosomal recessive juvenile parkinsonism. In 1 family, in which an autosomal dominant mode of inheritance was suspected, multiple mutant alleles were identified. Although a wide range of ages at onset was observed, there was no correlation between age at onset and genotype.

The gross and histopathological findings in the brain and spinal cord of five Alaskan Husky dogs with a novel incapacitating and ultimately fatal familial and presumed hereditary neurodegenerative disorder are described. Four dogs presented with neurological deficits before the age of 1 year (7-11 months) and one animal at 2.5 years old. Clinical signs in all dogs were of acute onset and included ataxia, seizures, behavioral abnormalities, blindness, facial hypalgesia and difficulties in prehension of food. In animals allowed to survive, the disease was static but with frequent recurrences. Pathological findings were limited to the central nervous system. Grossly visible bilateral and symmetrical cavitated foci were consistently present in the thalamus with variable extension into the caudal brain stem. Microscopic lesions were more widespread and included foci of bilateral and symmetrical degeneration in the basal nuclei, midbrain, pons and medulla, as well as multifocal lesions at the base of sulci in the cerebral cortex and in the gray matter of cerebellar folia in the ventral vermis. Neuronal loss with concomitant neuronal sparing, spongiosis, vascular hypertrophy and hyperplasia, gliosis, cavitation and transient mixed inflammatory infiltration were the main histopathological findings. In addition, a population of reactive gemistocytic astrocytes with prominent cytoplasmic vacuolation was noted in the thalamus. Lesions of this nature in this distribution within the neuroaxis have not been reported in dogs. The neuropathological findings resemble Leigh's disease/subacute necrotizing encephalomyelopathy of man. Neuronal sparing in conjunction with apparently transient astrocytic vacuolation point to the possible pathogenetic role of astrocytes in the evolution of these lesions. An inherited metabolic derangement of unknown nature is postulated as the cause of this breed-specific disorder.

Olivopontocerebellar atrophy with retinal degeneration is a hereditary neurodegenerative disorder that belongs to the subtype II of the autosomal dominant cerebellar ataxias and is characterized by early-onset cerebellar and macular degeneration preceded by diagnostically useful tritan colorblindness. The gene mutated in the disease (SCA7) has been mapped to chromosome 3p12-13.5, and positional cloning identified the cause of the disease as CAG repeat expansion in this gene. The SCA7 gene product, ataxin-7, is an 897 amino acid protein with an expandable polyglutamine tract close to its N-terminus. No clues to ataxin-7 function have been obtained from sequence database searches. Here we report that ataxin-7 has a motif of ca. 50 amino acids, related to the phosphate-binding site of arrestins. To test the relevance of this sequence similarity, we introduced the putative ataxin-7 phosphate-binding site into visual arrestin and beta-arrestin. Both chimeric arrestins retain receptor-binding affinity and show characteristic high selectivity for phosphorylated activated forms of rhodopsin and beta-adrenergic receptor, respectively. Although the insertion of a Gly residue (absent in arrestins but present in the putative phosphate-binding site of ataxin-7) disrupts the function of visual arrestin-ataxin-7 chimera, it enhances the function of beta-arrestin-ataxin-7 chimera. Taken together, our data suggest that the arrestin-like site in the ataxin-7 sequence is a functional phosphate-binding site. The presence of the phosphate-binding site in ataxin-7 suggests that this protein may be involved in phosphorylation-dependent binding to its protein partner(s) in the cell.

Huntington’s disease is an autosomal dominant hereditary neurodegenerative disorder characterised by chorea, disturbed voluntary motor performance, behavioural changes and dementia. Despite the recent discovery of the gene defect (an expanded trinucleotide repeat) and its product huntingtin, no curative therapy is available to date. Confronted with genetically determined inevitable functional decline, psychosocial support remains the hallmark in the care for patients and relatives. Pharmacological treatment is limited to reduction of chorea and behavioural disturbances, often at the cost of further impairing voluntary movement and, consequently, functional capacity. Therefore, drug therapy should be highly individualised and generally restricted to patients with severely disabling symptoms.

Huntington's disease (HD) is a hereditary neurodegenerative disorder, characterized by motor, psychiatric, and cognitive symptoms. The genetic defect responsible for the onset of the disease, expansion of CAG repeats in exon 1 of the gene that codes for huntingtin, has been unambiguously identified. The mechanisms by which the mutation causes the disease are not completely understood yet. However, defects in the energy metabolism of affected cells, which may cause oxidative damage, have been proposed as underlying molecular mechanisms that participate in the etiology of the disease. In this chapter, we describe biochemical methods that allow us to determine striatal oxidative damage in transgenic mice and in the quinolinic acid-induced excitotoxicity model in rat, and establish the status of protective cellular systems. The excitotoxic model is acute, easier and faster to perform than the transgenic model, and can within a short period provide valuable data to try new therapeutic strategies. The methods described in this chapter permit us to link the kynurenine pathway with the cascade of toxic and harmful reactions that cause the damage observed in HD. We consider that determining the mechanisms inducing oxidative damage in two different models of HD will allow the testing of drugs or other therapeutic strategies with antioxidant activities.

Huntington's disease (HD) is a rare hereditary neurodegenerative disorder characterized in over 90 percent of cases by chorea as the presenting motor symptom. We report a 54-year-old male who presented with Parkinsonism as the initial symptom of the disease. Genetic analysis revealed expansion of 40 CAG repeats, and brain MRI showed both severe caudate nuclei and cortical atrophy. Single-photon emission computed tomography (SPECT) imaging of the dopamine transporter showed nigrostriatal pathway degeneration. Here, we also describe his 2 years of clinical followup after ensuing dopaminergic stimulation.

Huntington's disease (HD) is neither a fatal hereditary neurodegenerative disorder without satisfactory treatments nor a cure. It is caused by a CAG repeat expansion in the huntingtin gene. The clinical symptoms involve motor-, cognitive- and psychiatric disturbances. Recent studies have shown that non-motor symptoms and signs, such as mood changes, sleep disturbances and metabolic alterations often occur before the onset of overt motor impairments. The hypothalamus is one of the main regulators of emotion, sleep and metabolism, and it is therefore possible that dysfunction of the hypothalamus and neuroendocrine circuits may, at least partly, be responsible for these non-motor symptoms in HD. Several hypothalamic and neuroendocrine changes have now been identified in clinical HD as well as in rodent models of the disease. These changes could be important both in the pathogenesis of HD, constitute biomarkers to track disease progression as well as to provide novel therapeutic targets for this devastating disease. The current state of knowledge in the area of hypothalamic and neuroendocrine changes in both patients and rodent models of HD is summarized in this review, and their potential as targets for novel treatment paradigms are discussed.

Distal hereditary motor neuronopathy with pyramidal features (dHMNP) is a hereditary neurodegenerative disorder characterised by the presence of upper and lower motor neuron signs. The pathophysiological mechanisms underlying these clinical findings remain elusive. Given that cortical hyperexcitability appears to underlie neurodegeneration in amyotrophic lateral sclerosis (ALS), a disorder that may clinically resemble dHMNP, the present study applied novel cortical excitability studies to further investigate the pathophysiological mechanisms in dHMNP.Threshold tracking transcranial magnetic stimulation (TMS) studies were undertaken using a 90 mm circular coil. Peripheral nerve excitability was performed by stimulating the median nerve at the wrist, with recording made over the abductor pollicis brevis muscle. Studies were undertaken in six dHMNP and 52 ALS patients, and compared with 55 normal controls.Central motor conduction time (CMCT) was significantly prolonged in dHMNP (dHMNP 7.7 (SEM 0.7) ms; ALS 4.9 (0.3) ms; controls 5.1 (0.2) ms, p0.01). Short interval intacortical inhibition (SICI) was significantly reduced in ALS patients (0.8 (0.8)%) when compared with dHMNP (6.4 (0.7)%, p0.0001) and controls (8.6 (1.1)%, p0.0001). Reduction in SICI was accompanied by significant increases in the magnetic stimulus-response curve gradient and intracortical facilitation, and reduction in cortical silent period duration in ALS, while all these parameters of cortical excitability were normal in dHMNP.The present study has established a prolonged CMCT and normal cortical excitability in dHMNP, thereby providing further support for the hypothesis that cortical hyperexcitability underlies neurodegeneration in ALS.

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expanded CAG repeat in the HD gene that results in cortical and striatal degeneration, and mutant huntingtin aggregation. Current treatments are unsatisfactory. R6 transgenic mice replicate many features of the human condition, show early onset of symptoms and fast disease progression, being one of the most used models for therapy screening. Here we review the therapies that have been tested in these mice: environmental enrichment, inhibition of histone deacetylation and methylation, inhibition of misfolding and oligomerization, transglutaminase inhibition, rescue of metabolic impairment, amelioration of the diabetic phenotype, use of antioxidants, inhibition of excitotoxicity, caspase inhibition, transplantation, genetic manipulations, and restoration of neurogenesis. Although many of these treatments were beneficial in R6 mice, they may not be as effective in HD patients, and thus the search for a combination of therapies that will rescue the human condition continues.

Publisher Summary Huntington Disease (HD) is a hereditary neurodegenerative disorder that is characterized by a triad of motor, cognitive, and psychiatric symptoms, which begin insidiously and progress over many years, eventually leading to death. HD is an autosomal dominant disorder and each offspring of an affected individual has a 50% chance of inheriting the disease-causing allele. The primary focus of this chapter is to encourage the efficient screening of new therapeutic agents for the treatment of HD in pre-clinical transgenic mouse models and to facilitate the translation of these studies into human clinical trials. Better animal disease models and more accurate pre-clinical evaluation of potential therapeutic agents will help prevent the massive expense and the disappointment of non-informative or unsuccessful clinical trials. The most promising new treatments that are effective in the various models of HD need to be rapidly evaluated for use in human clinical trials. Despite impressive recent advances in the understanding of the pathogenesis of HD, there are currently no known treatments that halt the progression or delay the clinical onset. Appropriate studies in pre-clinical models of HD will lead to the development of new treatments that prevent or slow down the progression of this devastating disease and will translate into improved quality of life, greater self-sufficiency, and longer more productive lives for individuals with HD.

Huntington disease (HD) is a hereditary neurodegenerative disorder caused by an expanded number of CAG repeats in the huntingtin gene. A hallmark of HD is unintended weight loss, the cause of which is unknown. In order to elucidate the underlying mechanisms of weight loss in HD, we studied its relation to other disease characteristics including motor, cognitive, and behavioral disturbances and CAG repeat number.In 517 patients with early stage HD, we applied mixed-effects model analyses to correlate weight changes over 3 years to CAG repeat number and various components of the Unified Huntington's Disease Rating Scale (UHDRS). We also assessed the relation between CAG repeat number and body weight and caloric intake in the R6/2 mouse model of HD.In patients with HD, mean body mass index decreased with -0.15 units per year (p < 0.001). However, no single UHDRS component, including motor, cognitive, and behavioral scores, was independently associated with the rate of weight loss. Patients with HD with a higher CAG repeat number had a faster rate of weight loss. Similarly, R6/2 mice with a larger CAG repeat length had a lower body weight, whereas caloric intake increased with larger CAG repeat length.Weight loss in Huntington disease (HD) is directly linked to CAG repeat length and is likely to result from a hypermetabolic state. Other signs and symptoms of HD are unlikely to contribute to weight loss in early disease stages. Elucidation of the responsible mechanisms could lead to effective energy-based therapeutics.

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by cognitive, psychiatric, behavioural and motor disturbances. Although the course of HD is also frequently complicated by unintended weight loss, sleep disturbances and autonomic nervous system dysfunction, the aetiology of these signs and symptoms remains largely unknown. In recent years, many novel findings from both animal and human studies have emerged that indicate considerable hypothalamic, endocrine and metabolic alterations in HD. However, a comprehensive overview of these findings is lacking and their precise clinical significance is far from clear. Therefore, in this review we attempt to put these recent developments in the field into perspective by integrating them with previous findings in a comprehensible manner, and by discussing their clinical relevance, with a special focus on body weight, sleep and autonomic functions in HD, which will also allow for the identification of future lines of research in this area.