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Glial cell line-derived neurotrophic factor (GDNF) is a strong candidate agent in the neuroprotective treatment of Parkinson's disease (PD). We investigated whether adeno-associated viral (AAV) vector-mediated delivery of a GDNF gene in a delayed manner could prevent progressive degeneration of dopaminergic (DA) neurons, while preserving a functional nigrostriatal pathway. Four weeks after a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA), rats received injection of AAV vectors expressing GDNF tagged with FLAG peptide (AAV-GDNFflag) or β-galactosidase (AA V-LacZ) into the lesioned striatum. Immunostaining for FLAG demonstrated retrograde transport of GDNFflag to the substantia nigra (SN). The density of tyrosine hydroxylase (TH)-positive DA fibers in the striatum and the number of TH-positive or cholera toxin subunit B (CTB, neuronal tracer)-labeled neurons in the SN were significantly greater in the AAV-GDNFflag group than in the AAV-LacZ group. Dopamine levels and those of its metabolites in the striatum were remarkably higher in the AAV-GDNFflag group compared with the control group. Consistent with anatomical and biochemical changes, significant behavioral recovery was observed from 4-20 weeks following AAV-GDNFflag injection. These data indicate that a delayed delivery of GDNF gene using AAV vector is efficacious even 4 weeks after the onset of progressive degeneration in a rat model of PD. [ABSTRACT FROM AUTHOR]

Reduced muscle mass has been associated with the progression and prognosis of amyotrophic lateral sclerosis (ALS). However, it remains unclear whether decreased muscle mass is a risk factor for ALS or a consequence of motor neuron degeneration. Recently, serum creatinine-to-cystatin C ratio (CCR) have emerged as promising biomarkers for assessing muscle mass. We aimed to explore the association between CCR and the incidence of ALS using data from the UK Biobank. Between 2006 and 2010, 446,945 participants were included in the baseline. CCR was calculated as the ratio of serum creatinine to cystatin C. Cox regression models were used to analyze the relationship between CCR and ALS incidence. Furthermore, subgroup analyses were conducted to investigate potential covariates in these relationships. After adjusting for all covariates, the multivariate Cox regression analysis revealed a significant association between decreased CCR and an increased risk of ALS (hazard ratio (HR) = 0.990, 95% confidence interval (CI): 0.982–0.999, P = 0.026). Participants were stratified into groups based on CCR tertiles. Compared with participants in the highest tertiles of CCR, those in the lowest (HR = 1.388, 95% CI: 1.032–1.866, P = 0.030) and medium tertiles (HR = 1.348, 95% CI: 1.045–1.739, P = 0.021) had an increased risk of ALS incidence. Subgroup analysis showed that the relationship between CCR and ALS incidence was particularly significant among participants aged < 65 years (CCR tertile 1: HR = 1.916, 95% CI: 1.366–2.688, P < 0.001; CCR tertile 2: HR = 1.699, 95% CI: 1.267–2.278, P < 0.001). The present results demonstrate that lower CCR is significantly associated with a higher risk of ALS. [ABSTRACT FROM AUTHOR]

Recombinant adeno-associated viruses (rAAVs) have emerged as an attractive tool for gene delivery, and demonstrated tremendous promise in gene therapy and gene editing—therapeutic modalities with potential "one-and-done" treatment benefits compared to conventional drugs. Given their tropisms for the central nervous system (CNS) across various species including humans, rAAVs have been extensively investigated in both pre-clinical and clinical studies targeting neurodegenerative disease. However, major challenges remain in the application of rAAVs for CNS gene therapy, such as suboptimal vector design, low CNS transduction efficiency and specificity, and therapy-induced immunotoxicity. Therefore, continuing efforts are being made to optimize the rAAV vectors from their "core" genetic payloads to their "coat" or capsid structure. In this review, we describe current approaches for rAAV vector design tailored for transgene expression in the CNS, summarize the development of CNS-targeting AAV serotypes, and highlight recent advancements in AAV capsid engineering, aimed at generating a new generation of rAAVs with improved CNS tropism. Additionally, we discuss various administration routes for delivering rAAVs to the CNS and provide an overview of AAV-mediated gene therapies currently under investigation in clinical trials for the treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration, leading to neuromuscular junction (NMJ) dismantling and severe muscle atrophy. The nuclear receptor interaction protein (NRIP) functions as a multifunctional protein. It directly interacts with calmodulin or α-actinin 2, serving as a calcium sensor for muscle contraction and maintaining sarcomere integrity. Additionally, NRIP binds with the acetylcholine receptor (AChR) for NMJ stabilization. Loss of NRIP in muscles results in progressive motor neuron degeneration with abnormal NMJ architecture, resembling ALS phenotypes. Therefore, we hypothesize that NRIP could be a therapeutic factor for ALS. Methods: We used SOD1 G93A mice, expressing human SOD1 with the ALS-linked G93A mutation, as an ALS model. An adeno-associated virus vector encoding the human NRIP gene (AAV-NRIP) was generated and injected into the muscles of SOD1 G93A mice at 60 days of age, before disease onset. Pathological and behavioral changes were measured to evaluate the therapeutic effects of AAV-NRIP on the disease progression of SOD1 G93A mice. Results: SOD1 G93A mice exhibited lower NRIP expression than wild-type mice in both the spinal cord and skeletal muscle tissues. Forced NRIP expression through AAV-NRIP intramuscular injection was observed in skeletal muscles and retrogradely transduced into the spinal cord. AAV-NRIP gene therapy enhanced movement distance and rearing frequencies in SOD1 G93A mice. Moreover, AAV-NRIP increased myofiber size and slow myosin expression, ameliorated NMJ degeneration and axon terminal denervation at NMJ, and increased the number of α-motor neurons (α-MNs) and compound muscle action potential (CMAP) in SOD1 G93A mice. Conclusions: AAV-NRIP gene therapy ameliorates muscle atrophy, motor neuron degeneration, and axon terminal denervation at NMJ, leading to increased NMJ transmission and improved motor functions in SOD1 G93A mice. Collectively, AAV-NRIP could be a potential therapeutic drug for ALS. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders are characterized by mitochondrial dysfunction and subsequently oxidative stress, inflammation, and apoptosis that contribute to neuronal cytotoxicity and degeneration. Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) diseases are three of the major neurodegenerative diseases. To date, researchers have found various natural phytochemicals that could potentially be used to treat neurodegenerative diseases. Particularly, the application of natural phenolic compounds has gained significant traction in recent years, driven by their various biological activities and therapeutic efficacy in human health. Polyphenols, by modulating different cellular functions, play an important role in neuroprotection and can neutralize the effects of oxidative stress, inflammation, and apoptosis in animal models. This review focuses on the current state of knowledge on phenolic compounds, including phenolic acids, flavonoids, stilbenes, and coumarins, as well as their beneficial effects on human health. We further provide an overview of the therapeutic potential and mechanisms of action of natural dietary phenolics in curing neurodegenerative diseases in animal models. [ABSTRACT FROM AUTHOR]

Parkinson's disease, the second most common neurodegenerative disorder worldwide, is characterized by the accumulation of protein deposits in the dopaminergic neurons. These deposits are primarily composed of aggregated forms of α-Synuclein (α-Syn). Despite the extensive research on this disease, only symptomatic treatments are currently available. However, in recent years, several compounds, mainly of an aromatic character, targeting α-Syn self-assembly and amyloid formation have been identified. These compounds, discovered by different approaches, are chemically diverse and exhibit a plethora of mechanisms of action. This work aims to provide a historical overview of the physiopathology and molecular aspects associated with Parkinson's disease and the current trends in small compound development to target α-Syn aggregation. Although these molecules are still under development, they constitute an important step toward discovering effective anti-aggregational therapies for Parkinson's disease. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a complex multifactorial disorder that is not yet fully surmised, and it is only when such a disease is tackled on multiple levels simultaneously that we should expect to see fruitful results. Gene therapy is a modern medical practice that theoretically and, so far, practically, has demonstrated its capability in joining the battle against PD and other complex disorders on most if not all fronts. This review discusses how gene therapy can efficiently replace current forms of therapy such as drugs, personalized medicine or invasive surgery. Furthermore, we discuss the importance of enhancing delivery techniques to increase the level of transduction and control of gene expression or tissue specificity. Importantly, the results of current trials establish the safety, efficacy and applicability of gene therapy for PD. Gene therapy's variety of potential in interfering with PD's pathology by improving basal ganglial circuitry, enhancing dopamine synthesis, delivering neuroprotection or preventing neurodegeneration may one day achieve symptomatic benefit, disease modification and eradication. [ABSTRACT FROM AUTHOR]

The role of cell transplantation therapy and gene therapy in the treatment of Parkinson's disease (PD) has attracted more and more attention. It has developed from laboratory research tools to clinical products for patients. The purpose of cell transplantation therapy in PD is to replace degenerated midbrain dopamine neurons and restore dopamine neurotransmission in the denervation of the nigrostriatal pathway. Gene therapy works by introducing genetic material to slow down the degeneration of dopamine neurons and restore dopaminergic signaling transduction. Using neurotrophic factor and delivery methods for neurotrophic factor have entered clinical trials. It can also intervene in the pathological process of α-synuclein (α-Syn) mediated neurodegeneration. This paper reviews the latest progress of cell transplantation therapy and gene therapy for PD, and looks forward to the future treatment strategies. [ABSTRACT FROM AUTHOR]

It is without doubt that the gene therapy field is currently in the spotlight for the development of new therapeutics targeting unmet medical needs. Thus, considering the gene therapy scenario, neurological diseases in general and neurodegenerative disorders in particular are emerging as the most appealing choices for new therapeutic arrivals intended to slow down, stop, or even revert the natural progressive course that characterizes most of these devastating neurodegenerative processes. Since an extensive coverage of all available literature is not feasible in practical terms, here emphasis was made in providing some advice to beginners in the field with a narrow focus on elucidating the best delivery route available for fulfilling any given AAV-based therapeutic approach. Furthermore, it is worth nothing that the number of ongoing clinical trials is increasing at a breath-taking speed. Accordingly, a landscape view of preclinical and clinical initiatives is also provided here in an attempt to best illustrate what is ongoing in this quickly expanding field. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, defined as motor and non-motor symptoms associated with the loss of dopaminergic neurons and a decreased release of dopamine (DA). Currently, PD patients are believed to have a neuropathological basis denoted by the presence of Lewy bodies (LBs) or Lewy neurites (LNs), which mostly comprise α-synuclein (α-syn) inclusions. Remarkably, there is a growing body of evidence indicating that the inclusions undergo template-directed aggregation and propagation via template-directed among the brain and peripheral organs, mainly in a prion-like manner. Interestingly, some studies reported that an integral loop was reminiscent of the mechanism of Parkinson's disease, denoting that α-syn as prionoid was transmitted from the periphery to the brain via specific pathways. Also the systematic life cycle of α-syn in the cellular level is illustrated. In this review, we critically assess landmark evidence in the field of Parkinson's disease with a focus on the genesis and prion-like propagation of the α-syn pathology. The anatomical and cell-to-cell evidences are discussed to depict the theory behind the propagation and transferred pathways. Furthermore, we highlight effective therapeutic perspectives and clinical trials targeting prion-like mechanisms. Major controversies surrounding this topic are also discussed. [ABSTRACT FROM AUTHOR]

Abstract: The failure of DNA ligases to complete their catalytic reactions generates cytotoxic adenylated DNA strand breaks. The APTX RNA‐DNA deadenylase protects genome integrity and corrects abortive DNA ligation arising during ribonucleotide excision repair and base excision DNA repair, and APTX human mutations cause the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1). How APTX senses cognate DNA nicks and is inactivated in AOA1 remains incompletely defined. Here, we report X‐ray structures of APTX engaging nicked RNA‐DNA substrates that provide direct evidence for a wedge‐pivot‐cut strategy for 5′‐AMP resolution shared with the alternate 5′‐AMP processing enzymes POLβ and FEN1. Our results uncover a DNA‐induced fit mechanism regulating APTX active site loop conformations and assembly of a catalytically competent active center. Further, based on comprehensive biochemical, X‐ray and solution NMR results, we define a complex hierarchy for the differential impacts of the AOA1 mutational spectrum on APTX structure and activity. Sixteen AOA1 variants impact APTX protein stability, one mutation directly alters deadenylation reaction chemistry, and a dominant AOA1 variant unexpectedly allosterically modulates APTX active site conformations. [ABSTRACT FROM AUTHOR]

The field of gene therapy has recently witnessed a number of major conceptual changes. Besides the traditional thinking that comprises the use of viral vectors for the delivery of a given therapeutic gene, a number of original approaches have been recently envisaged, focused on using vectors carrying genes to further modify basal ganglia circuits of interest. It is expected that these approaches will ultimately induce a therapeutic potential being sustained by gene-induced changes in brain circuits. Among others, at present, it is technically feasible to use viral vectors to (1) achieve a controlled release of neurotrophic factors, (2) conduct either a transient or permanent silencing of any given basal ganglia circuit of interest, (3) perform an in vivo cellular reprogramming by promoting the conversion of resident cells into dopaminergic-like neurons, and (4) improving levodopa efficacy over time by targeting aromatic l-amino acid decarboxylase. Furthermore, extensive research efforts based on viral vectors are currently ongoing in an attempt to better replicate the dopaminergic neurodegeneration phenomena inherent to the progressive intraneuronal aggregation of alpha-synuclein. Finally, a number of incoming strategies will soon emerge over the horizon, these being sustained by the underlying goal of promoting alpha-synuclein clearance, such as, for instance, gene therapy initiatives based on increasing the activity of glucocerebrosidase. To provide adequate proof-of-concept on safety and efficacy and to push forward true translational initiatives based on these different types of gene therapies before entering into clinical trials, the use of non-human primate models undoubtedly plays an instrumental role. [ABSTRACT FROM AUTHOR]

Our aim was to investigate whether tangeretin, a citrus flavonoid, was able to prevent neuroinflammation and improve dementia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced rodent model of Parkinson's disease (PD). MPTP-HCl was infused into the substantia nigra pars compacta of male Sprague-Dawley rats. Tangeretin (50, 100 or 200 mg/kg body weight) was administered orally starting 3 days prior to MPTP injection and was continued for 20 days following injection. MPTP-lesioned rats revealed motor dysfunction in bar test and rota rod tests. Deficits in working memory and object recognition function were also observed following MPTP induction. Tangeretin treatment significantly attenuated the memory deficits and improved motor functions and cognition. Immunohistochemical analysis reveals the protective effects of tangeretin against MPTP lesion-induced dopaminergic degeneration and hippocampal neuronal loss. Tangeretin reduced expression of inflammatory mediators-COX-2, iNOS-as well reduced the levels of cytokines-interleukins (IL)-IL-1β, IL-6 and IL-2. The experimental data suggest tangeretin as an effective candidate drug with potential for prevention and treatment of neuroinflammation and dementia associated with PD. [ABSTRACT FROM AUTHOR]

The effects of germinated brown rice (GBR) on the motor deficits and the dopaminergic (DA) cell death were investigated in Parkinson's-like disease (PD) rats. Reactive oxidative species generated by chronic subcutaneous injection of rotenone (RT) lead to neuronal apoptosis particularly in the nigrostriatal DA system and produce many features of PD, bradykinesis, postural instability and rigidity. In this study, 4-phenylbutyric acid (4-PBA), previously reported to inhibit RT-induced DA cell death, was used as the positive control. Results show that pretreatment with GBR as well as 4-PBA significantly enhanced the motor activity after RT injection, and GBR affected significantly in open field test, only in the ambulation but not the mobility duration, and ameliorated the time to orient down (t-turn) and total time to descend the pole (t-total) in pole test as compared to RT group, but significantly lowered both t-turn and t-total only in 4-PBA group. The percentage of apoptotic cells in brain measured by flow cytometry and the inflammatory effect measured by ELISA of TNF-α showed significant increase in RT group as compared to the control (CT) group at P < 0.05. Apoptotic cells in RT group (85.98 %) showed a significant ( P < 0.05) increase versus CT group (17.50 %), and this effect was attenuated in GBR+RT group by decreasing apoptotic cells (79.32 %), whereas, increased viable cells (17.94 %) versus RT group (10.79 %). GBR in GBR + RT group could decrease TNF-α both in the serum and in brain. In summary, GBR showed a neuroprotective effect in RT-induced PD rats, and it may be useful as a value-added functional food to prevent neurodegenerative disease or PD. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease primarily characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. It is increasingly accepted that the pathological process leading to ALS is the result of multiple disease mechanisms that operate within motor neurons and other cell types both inside and outside the central nervous system. The implication of skeletal muscle has been the subject of a number of studies conducted on patients and related animal models. In this review, we describe the features of ALS muscle pathology and discuss on the contribution of muscle to the pathological process. We also give an overview of the therapeutic strategies proposed to alleviate muscle pathology or to deliver curative agents to motor neurons. ALS muscle mainly suffers from oxidative stress, mitochondrial dysfunction and bioenergetic disturbances. However, the way by which the disease affects different types of myofibers depends on their contractile and metabolic features. Although the implication of muscle in nourishing the degenerative process is still debated, there is compelling evidence suggesting that it may play a critical role. Detailed understanding of the muscle pathology in ALS could, therefore, lead to the identification of new therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) influences nigral dopaminergic neurons via autocrine and paracrine mechanisms. The reduction of BDNF expression in Parkinson's disease substantia nigra (SN) might contribute to the death of dopaminergic neurons because inhibiting BDNF expression in the SN causes parkinsonism in the rat. This study aimed to demonstrate that increasing BDNF expression in dopaminergic neurons of rats with one week of 6-hydroxydopamine lesion recovers from parkinsonism. The plasmids phDAT-BDNF-flag and phDAT-EGFP, coding for enhanced green fluorescent protein, were transfected using neurotensin (NTS)-polyplex, which enables delivery of genes into the dopaminergic neurons via neurotensin-receptor type 1 (NTSR1) internalization. Results: Two weeks after transfections, RT-PCR and immunofluorescence techniques showed that the residual dopaminergic neurons retain NTSR1 expression and susceptibility to be transfected by the NTS-polyplex. phDAT-BDNF-flag transfection did not increase dopaminergic neurons, but caused 7-fold increase in dopamine fibers within the SN and 5-fold increase in innervation and dopamine levels in the striatum. These neurotrophic effects were accompanied by a significant improvement in motor behavior. Conclusions: NTS-polyplex-mediated BDNF overexpression in dopaminergic neurons has proven to be effective to remit hemiparkinsonism in the rat. This BDNF gene therapy might be helpful in the early stage of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Since identification of mutations in the ATM gene leading to ataxia-telangiectasia, enormous efforts have been devoted to discovering the roles this protein plays in DNA repair as well as other cellular functions. Even before the identification of ATM mutations, it was clear that other diseases with different genomic loci had very similar neurological symptoms. There has been significant progress in understanding why cancer and immunodeficiency occur in ataxia-telangiectasia even though many details remain to be determined, but the field is no closer to determining why the nervous system requires ATM and other DNA repair genes. Even though rodent disease models have similar DNA repair abnormalities as the human diseases, they have no consistent, robust neuropathological phenotype making it difficult to understand the neurological underpinnings of disease. Therefore, it may be useful to reassess the neurological and neuropathological characteristics of ataxia-telangiectasia in human patients to look for potential commonalities in DNA repair diseases that result in ataxia. In doing so, it is clear that ataxia-telangiectasia and similar diseases share neurological features other than merely ataxia, such as length-dependent motor and sensory neuropathies, and that the neuroanatomical localization for these symptoms is understood. Cells affected in ataxia-telangiectasia and similar diseases are some of the largest single nucleated cells in the body. In addition, a subset of these diseases also has extrapyramidal movements and oculomotor apraxia. These neurological and neuropathological similarities may indicate a common DNA repair related pathogenesis with very large cell size as a critical risk factor. [ABSTRACT FROM AUTHOR]

In addition to dopaminergic neuron loss, it is clear that Parkinson disease includes other pathological changes, including loss of additional neuronal populations. As a means of addressing multiple pathological changes with a single therapeutically-relevant approach, we employed delayed transplantation of a unique class of astrocytes, GDAs BMP, that are generated in vitro by directed differentiation of glial precursors. GDAs BMP produce multiple agents of interest as treatments for PD and other neurodegenerative disorders, including BDNF, GDNF, neurturin and IGF1. GDAs BMP also exhibit increased levels of antioxidant pathway components, including levels of NADPH and glutathione. Delayed GDABMP transplantation into the 6-hydroxydopamine lesioned rat striatum restored tyrosine hydroxylase expression and promoted behavioral recovery. GDABMP transplantation also rescued pathological changes not prevented in other studies, such as the rescue of parvalbumin+ GABAergic interneurons. Consistent with expression of the synaptic modulatory proteins thrombospondin-1 and 2 by GDAs BMP, increased expression of the synaptic protein synaptophysin was also observed. Thus, GDAs BMP offer a multimodal support cell therapy that provides multiple benefits without requiring prior genetic manipulation. [ABSTRACT FROM AUTHOR]

Many experiments affirm the notion that augmentation of neurotrophic factors (NTFs) activity, especially brain-derived neurotrophic factors and glial cell-derived neurotrophic factors, could prevent or halt the progress of neurodegeneration in Parkinson's disease (PD). In this study, we investigated the therapeutic accomplishment of geraniol (GE 100 mg/kg) on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mice model of PD. Current investigation proved that pretreatment with GE ameliorates the MPTP-induced alterations in behavioral, biochemical, immunohistochemical, and immunoblotting manifestations in mice. Systematically, the loss of dopaminergic neurons and reduced NTFs mRNA expressions induced by MPTP was ameliorated to a significant extent by pretreatment with GE. We found that GE confers a potent neuroprotective agent against MPTP-induced dopaminergic denervation and may become a potential therapeutic agent for PD and/or its progression. [ABSTRACT FROM AUTHOR]

Background: The impairment of the ubiquitin-proteasome system (UPS) is a cellular mechanism underlying the neurodegenerative process in Parkinson's disease (PD). A mouse model induced by the selective proteasome inhibitor lactacystin targeting on substantia nigra has been demonstrated to be valuable in investigating etiopathogenesis and neuroprotection for PD. Objective: In the present study, we used adeno-associated virus type 2 vector (AAV2) encoding glial cell line-derived neurotrophic factor (GDNF) injected into the striatum of this animal model to test the effectiveness and possible mechanisms of GDNF gene therapy. Results: Our results showed that AAV2-mediated GDNF gene therapy significantly attenuated lactacystin-induced loss of nigral dopamine (DA) neurons and striatal DA levels. Furthermore, we found that GDNF protein is mostly expressed in astrocytes in the subventricular zone (SVZ) and dentate gyrus (DG). AAV2-mediated GDNF therapy can induce neurogenesis in the SVZ and DG, and increase the number of nigral newborn DA neurons. Conclusion: These data indicate that AAV2-mediated GDNF gene therapy can protect the nigral DA neurons from the UPS impairment-induced degeneration, which may partly result from the nigral DA neuron regeneration in the brain, and such experimental results may have implications for the treatment of PD. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The neuropathological hallmark of the majority of amyotrophic lateral sclerosis (ALS) and a class of frontotemporal lobar degeneration is ubiquitinated cytoplasmic aggregates composed of transactive response DNA binding protein 43 kDa (TDP-43). Genetic manipulation of TDP-43 in animal models has been used to study the protein's role in pathogenesis. Transgenic rodents for TDP-43 have recapitulated key aspects of ALS such as paralysis, loss of spinal motor neurons and muscle atrophy. Viral vectors are an alternate approach to express pathological proteins in animals. Use of the recombinant adeno-associated virus vector serotype 9 has permitted widespread transgene expression throughout the central nervous system after intravenous administration. Expressing TDP-43 in rats with this method produced a phenotype that was consistent with and similar to TDP-43 transgenic lines. Increased levels of TDP-43 in the nucleus are toxic to neurons and sufficient to produce ALS-like symptoms. Animal models based on TDP-43 will address the relationships between TDP-43 expression levels, pathology, neuronal loss, muscle atrophy, motor function and causative mechanisms of disease. New targets that modify TDP-43 function, or targets from previous ALS models and other models of spinal cord diseases, could be tested for efficacy in the recent rodent models of ALS based on TDP-43. The vector approach could be an important therapeutic channel because the entire spinal cord can be affected from a one-time peripheral administration. [ABSTRACT FROM AUTHOR]

Parkinson's disease is a progressive neurodegenerative disorder affecting, in part, dopaminergic motor neurons of the ventral midbrain and their terminal projections that course to the striatum. Symptomatic strategies focused on dopamine replacement have proven effective at remediating some motor symptoms during the course of disease but ultimately fail to deliver long-term disease modification and lose effectiveness due to the emergence of side effects. Several strategies have been experimentally tested as alternatives for Parkinson's disease, including direct cell replacement and gene transfer through viral vectors. Cellular transplantation of dopamine-secreting cells was hypothesized as a substitute for pharmacotherapy to directly provide dopamine, whereas gene therapy has primarily focused on restoration of dopamine synthesis or neuroprotection and restoration of spared host dopaminergic circuitry through trophic factors as a means to enhance sustained controlled dopamine transmission. This seems now to have been verified in numerous studies in rodents and nonhuman primates, which have shown that grafts of fetal dopamine neurons or gene transfer through viral vector delivery can lead to improvements in biochemical and behavioral indices of dopamine deficiency. However, in clinical studies, the improvements in parkinsonism have been rather modest and variable and have been plagued by graft-induced dyskinesias. New developments in stem-cell transplantation and induced patient-derived cells have opened the doors for the advancement of cell-based therapeutics. In addition, viral-vector-derived therapies have been developed preclinically with excellent safety and efficacy profiles, showing promise in clinical trials thus far. Further progress and optimization of these therapies will be necessary to ensure safety and efficacy before widespread clinical use is deemed appropriate. © 2011 Mount Sinai School of Medicine [ABSTRACT FROM AUTHOR]

Sporadic Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common neurodegenerative diseases and as such they represent major public health problems. Finding effective treatments for AD and PD represents an unmet and elusive goal largely because these diseases are chronic and progressive, and have a complicated and ill-understood pathogenesis. Although the underlying mechanisms are not fully understood, caffeine, the most commonly ingested psychoactive drug in the world, has been shown in human and animal studies to be protective against AD and PD. One mechanism implicated in the pathogenesis of AD and PD is blood-brain barrier (BBB) dysfunction and we reported recently that caffeine exerts protective effects against AD and PD at least in part by keeping the BBB intact. The present review focuses on the role of BBB dysfunction in the pathogenesis of AD and PD, caffeine's protective effects against AD and PD, and potential mechanisms whereby caffeine protects against BBB leakage. [ABSTRACT FROM AUTHOR]

Impaired trophic support of motor neurons appears to be an important pathogenic factor in amyotrophic lateral sclerosis (ALS). We investigated the mRNA expression of the pluripotent fibroblast growth factor 2 (FGF-2) and its receptors in post mortem spinal cord of ALS and control patients. FGF-2 and FGF receptor (FGFR) 1 and 2 transcripts were first studied in the spinal cord using RT-PCR. The cellular distribution of FGF-2 and FGFR mRNA in the spinal cord, motor cortex and brain stem was then assessed by in situ hybridization histochemistry. RT-PCR revealed the presence of FGF-2 and FGF receptor 1 and 2 transcripts with no obvious differences between ALS and control spinal cord. Comparing mRNA expression in the motoneuron-containing ventral horn with the clinically and neuropathologically spared dorsal horn of ALS spinal cord displayed similar expression levels. At the cellular level, we found a prominent neuronal expression of FGF-2 and FGFR1. Interestingly, both morphologically intact and damaged motoneurons showed positive staining for FGF-2 and FGFR1 transcripts. The distribution of cells expressing FGF-2 and FGFR1 transcripts showed no differences between ALS and controls. Our data suggest that FGF-2 and FGFR1 expression is preserved in the motor system in end stage ALS. [ABSTRACT FROM AUTHOR]

Neurotrophic factors have been widely suggested as a treatment for multiple diseases including motorneuron pathologies, like Amyotrophic Lateral Sclerosis. However, clinical trials in which growth factors have been systematically administered to Amyotrophic Lateral Sclerosis patients have not been effective, owing in part to the short half-life of these factors and their low concentrations at target sites. A possible strategy is the use of the atoxic C fragment of the tetanus toxin as a neurotrophic factor carrier to the motorneurons. The activity of trophic factors should be tested because their genetic fusion to proteins could alter their folding and conformation, thus undermining their neuroprotective properties. For this purpose, in this paper we explored the Brain Derived Neurotrophic Factor (BDNF) activity maintenance after genetic fusion with the C fragment of the tetanus toxin. We demonstrated that BDNF fused with the C fragment of the tetanus toxin induces the neuronal survival Akt kinase pathway in mouse cortical culture neurons and maintains its antiapoptotic neuronal activity in Neuro2A cells. [ABSTRACT FROM AUTHOR]

Many current studies of Parkinson's disease (PD) suggest that inflammation is involved in the neurodegenerative process. Tripchlorolide (TW397), a traditional Chinese herbal compound with anti-inflammatory and immunosuppressive properties, has been shown to protect dopaminergic neurons against, and restore their function after, the neurotoxicity induced by 1-methyl-4-phenylpyridinium ions in vitro. This study was designed to investigate the effect of TW397 in vivo in the PD model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned C57BL/6 mice. In the animals that received vehicle-only (i.e., no TW397) treatment with MPTP i.p. injection, the survival ratios of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the substantia nigra pars compacta and TH-IR fibres in the striatum were only 59 and 13%, respectively, compared with the normal controls. Intriguingly, in conjunction with MPTP, treatment with TW397, 1 µg/kg for 16 days, once per day, dramatically improved the survival rate of the TH-IR neurons and TH-IR fibres to 80 and 43% of the control. The treatment with TW397 also significantly improved the level of dopamine in the substantia nigra and striatum to 157 and 191%, respectively, of the MPTP- plus vehicle-treated group. In addition, in MPTP-treated animals the rota-rod performances of those treated with 0.5 or 1 µg/kg TW397 were significantly improved, by ∼2- and 3-fold, respectively, relative to vehicle-treated animals. The neuroprotective effect of TW397 was coincident with an attenuated astroglial response within the striatum. These data demonstrate a neuroprotective action of TW397 in vivo against MPTP toxicity, with important implications for the treatment of PD. [ABSTRACT FROM AUTHOR]

To evaluate variations in amyloid beta (Aβ) peptide pattern in cerebrospinal fluid (CSF) in neurodegenerative disorders. A recently established quantitative urea-based Aβ-sodium-dodecylsulfate-polyacrylamide-gel-electrophoresis with western immunoblot (Aβ-SDS-PAGE/immunoblot) revealed a highly conserved Aβ peptide (Aβ1-37, 1-38, 1-39, 1-40, 1-42) pattern in CSF. We asked whether the variation might be useful to further elucidate the overlap between or distinctions among neurodegenerative diseases in Aβ-processing. We used the Aβ-SDS-PAGE/immunoblot to investigate CSF for disease-specific Aβ peptide patterns. CSF samples from 96 patients with mainly clinically diagnosed Alzheimer’s disease ( n = 15), progressive supranuclear palsy ( n = 20), corticobasal degeneration ( n = 12), Parkinson’s disease ( n = 11), multiple systems atrophy ( n = 18), and dementia with Lewy-bodies ( n = 20) were analysed as well a comparison group ( n = 19). The Aβ peptide patterns varied between tauopathies and synucleinopathies and between all diseases and the comparison group, possibly due to the influence of tau and α-synuclein on Aβ-processing. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SNi). As neurotrophic factors support the survival and enhance the function of dopaminergic neurons, gene therapy using neurotrophic factors has become the center of interest. Thus, we focused on hepatocyte growth factor (HGF) as a neurotrophic and angiogenic growth factor. At 7 days before injection of 6-hydroxydopamine into the SNi, stereotaxic transfection of human HGF or lacZ plasmid was performed into the unilateral striatum of rats. Expression of human HGF in the injected sites could be detected in rats transfected with HGF plasmid DNA, using immunohistochemical staining. Consistently, human immunoreactive HGF protein could be detected at least up to 12 days after transfection. Interestingly, PD rats transfected with lacZ demonstrated amphetamine-induced rotational asymmetry. However, transfection of HGF plasmid DNA resulted in significant inhibition of abnormal rotation up to 24 weeks in a dose-dependent manner. Over 90% of dopaminergic neurons were lost in PD rats transfected with lacZ, whereas over 70% survived in rats transfected with HGF, as assessed by immunohistochemical staining. Overall, the present study demonstrated that overexpression of HGF prevented neuronal death in a PD rat model, providing a potential novel therapy for PD.Gene Therapy (2006) 13, 1639–1644. doi:10.1038/sj.gt.3302810; published online 22 June 2006 [ABSTRACT FROM AUTHOR]

Neurotrophic factors (NTFs) have the unique potential to support neuronal survival and to augment neuronal function in the injured and diseased nervous system. Numerous studies conducted over the last 20 years have provided evidence for the potent therapeutic potential of NTFs in animal models of neurodegenerative diseases. However, major obstacles for the therapeutic use of NTFs are the inability to deliver proteins across the blood-brain-barrier, and dose-limiting adverse effects resulting from the broad exposure of nontargeted structures to NTFs. Two recent developments have allowed NTFs’ promise to be truly tested for the first time: first, recent improvements in viral vectors that allow the targeted delivery of NTFs while providing a long-lasting supply and sufficient therapeutic doses of NTFs; and second, improved animal models developed in recent years. In this review, we will discuss some of the potential therapeutic applications of NTFs in neurodegenerative diseases and the potential contribution of disturbed neurotrophic factor signaling to neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

1. This study examined whether Paeoniflorin (PF), the major active components of Chinese herb Paeoniae alba Radix, has neuroprotective effect in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). 2. Subcutaneous administration of PF (2.5 and 5 mg kg(-1)) for 11 days could protect tyrosine hydroxylase (TH)-positive substantia nigra neurons and striatal nerve fibers from death and bradykinesia induced by four-dose injection of MPTP (20 mg kg(-1)) on day 8. 3. When given at 1 h after the last dose of MPTP, and then administered once a day for the following 3 days, PF (2.5 and 5 mg kg(-1)) also significantly attenuated the dopaminergic neurodegeneration in a dose-dependent manner. Post-treatment with PF (5 mg kg(-1)) significantly attenuated MPTP-induced proinflammatory gene upregulation and microglial and astrocytic activation. 4. Pretreatment with 0.3 mg kg(-1) 8-cyclopentyl-1,3-dipropylxanthine, an adenosine A1 receptor (A1AR) antagonist, 15 min before each dose of PF, reversed the neuroprotective and antineuroinflammatory effects of PF. 5. In conclusion, this study demonstrated that PF could reduce the MPTP-induced toxicity by inhibition of neuroinflammation by activation of the A1AR, and suggested that PF might be a valuable neuroprotective agent for the treatment of PD. [ABSTRACT FROM AUTHOR]

Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2-4/100,000), ataxia-telangiectasia (1-2.5/100,000) and early onset cerebellar ataxia with retained tendon reflexes (1/100,000). Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder), ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, α-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED), aprataxin in ataxia with oculomotor apraxia (AOA1), and senataxin in ataxia with oculomotor apraxia (AOA2). Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning), electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia. [ABSTRACT FROM AUTHOR]

In the past 3 decades, gene therapy has moved from a theoretical construct to an active field of basic research, animal studies, and clinical trials. In this article, we describe the conceptual basis underlying the use of gene therapy for diseases of the aging nervous system, the principal techniques used for gene delivery, and review preclinical animal studies in 4 different classes of neurologic dysfunction: 1) focal neuronal degeneration in the central nervous system; 2) global neuronal dysfunction in the central nervous system; 3) degenerative disease affecting components of the peripheral nervous system; and 4) intractable focal pain. The full potential of this approach will not be established until the human trials are completed. [ABSTRACT FROM AUTHOR]

Possible cell death mechanisms for pars compacta nigro-striatal dopamine neurons in Parkinson's disease include oxidative stress, inflammatory processes, nitric oxide, iron accumulation, glutamate toxicity and diminished neurotrophic factor responses. There is a notion that Parkinson's disease is not a single disorder but a syndrome that can be initiated by several factors. Because of limitations of biochemical methods in the global analysis of neuronal death, a full picture of events has not been established. However, recently developed cDNA microarray or microchips, in which the global expression of thousands of genes can be assessed simultaneously, is changing the prospect for understanding the disease process, its progression, response to drugs, etc. The neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is considered the most valid model of Parkinson's disease. We employed the technique of cDNA microarray gene expression to determine the mechanism of action of MPTP in mouse substantia nigra. Also, we studied neuroprotective processes induced by several compounds, including R-apomorphine and the green tea polyphenol epigallo-catechin-3-gallate (EGCG). This was done in two ways: (1) the time-dependent acute effect of MPTP, for determining which of the initial genes might lead to dopamine neuron death and (2) gene expression at the time of MPTP-induced dopamine neuron death. We observed that early (acute MPTP) gene expression differs from effects seen at the time of death (chronic MPTP), and that early gene changes are crucial for setting into action genes that eventually cause dopamine neuron death. Furthermore, this process is a cascade of 'domino' effects, some of which were previously established by biochemical means. However, our findings show an additional large number of events previously unknown. The neuroprotective drugs reversed some but not all of the gene expression, suggesting involvement of these genes in the neurodegenerative process. Because of the profound complexity of 'domino' effect it is now reasonable to understand why a single neuroprotective drug has not shown clinical neuroprotective efficacy. Future multi neuroprotective drugs may be necessary for treatment of not only Parkinson's disease, but other neurodegenerative diseases (e.g. Alzheimer's disease) and detrimental states (e.g. ischaemia). [ABSTRACT FROM AUTHOR]

Recently, we reported specific brain gene expression changes in the chronic MPTP model in the late stage of degeneration, employing cDNA expression array, which indicate a “domino” cascade of events involved in neuronal cell death. In an attempt to elucidate early gene expression profile in the region of the substantia nigra (SN) and the striatum of acute MPTP-treated mice (3–24 h), we elected a restricted number of genes affected by the long-term MPTP treatment, and their expression was examined. Specifically, we detected alterations in the expression of genes implicated in oxidative-stress, inflammatory processes, signal transduction and glutamate toxicity. These pro-toxic genes appear to be compensated by the elevated expression in trophic factors and antioxidant defenses, which are also activated by short exposure to MPTP. The time course of these gene expression changes indicates the importance of investigating the early gene cascade of events occurring prior to late nigrostriatal dopamine neuronal cell death. [ABSTRACT FROM AUTHOR]

Summary. Animal models are a very important approach to study the pathogenesis and therapeutic intervention strategies of human diseases. Since many human disorders do not arise spontaneously in animals, characteristic functional changes have to be mimicked by neurotoxic agents. For instance, the application of the dopaminergic neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is able to produce striking similarities to Parkinson's disease (PD) diagnosed in humans. MPTP is thought to selectively damage dopaminergic neurons predominantly those originating in the substantia nigra pars compacta (SNc) which leads to impaired dopaminergic neurotransmission accompanied by a loss of dopaminergic nerve terminals in the striatum. MPTP-induced neurochemical, behavioral, and histopathological alterations replicate very closely the clinical symptoms of PD patients, which will be discussed in this paper and render the MPTP model currently the most favored PD model to study therapeutic intervention strategies in an easy and reliable way in preclinical studies. We and many other research groups propose that the knowledge about the neurotoxic mechanisms of MPTP such as mitochondrial dysfunction with breakdown of energy metabolism and free radical production will help us to understand the underlying mechanisms of PD, which are not fully understood yet. In particular, the novel aspects of inflammatory processes and the involvement of reactive nitrogen species in addition to reactive oxygen species seem to be important milestones for a better understanding of the neurodegenerative effects of MPTP. In this review we focus on the MPTP mouse model which is easy practicable and widely used in neuroscience research and draw comparisons to the human pathology in PD. [ABSTRACT FROM AUTHOR]

To establish the possible roles of oxidative stress, inflammatory processes and other unknown mechanisms in neurodegeneration, we investigated brain gene alterations in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of Parkinson's disease using Atlas mouse cDNA expression array membrane. The expression of 51 different genes involved in oxidative stress, inflammation, glutamate and neurotrophic factors pathways as well as in still undefined processes, such as cell cycle regulators and signal transduction molecules, was differentially affected by the treatment. The present study indicates the involvement of an additional cascade of events that might act in parallel to oxidative stress and inflammation to converge eventually into a common pathway leading to neurodegeneration. The attenuation of these gene changes by R-apomorphine, an iron chelator-radical scavenger drug, supports our previous findings in vivo where R-apomorphine was neuroprotective. [ABSTRACT FROM AUTHOR]

Neurotrophic factors are compounds that enhance neuronal survival and differentiation. Most of these compounds exert their pharmacological actions on selective types of neurons, and therefore, are considered promising new therapeutic agents for the treatment of different neurodegenerative disorders characterized by selective degeneration of certain neuronal groups. Those compounds have been used in humans for several neurological disorders including amyotrophic lateral sclerosis - ciliary derived neurotrophic factor (CNTF) and brain derived neurotrophic factor (BDNF), Alzheimer's disease and peripheral neuropathy - nerve growth factor (NGF) and Parkinson's disease (PD) - glial derived neurotrophic factor (GDNF). In spite of well founded clinical experiments by previous experimental work in animal models some of these trials have been negative. For instance, animal models of PD have shown that several neurotrophic factors, including GDNF and other compounds, reduce apoptosis and increase resistance of dopamine neurons to neurotoxins in vitro. These compounds prevent or recover the damage to dopamine neurons of rodents and primates produced by chemical or mechanical acute lesions including 6-OHDA, MPTP, methamphetamine and axotomy. The differences between the promising results obtained in experimental models and the lack of clinical results or excessive toxicity found in humans could be attributed to the following reasons: (a) Lack of relevance between the pathogenesis of the experimental lesion and the corresponding neurodegenerative disorder. (b) Poor correlation between results obtained in acute, self-limited, selective deficit produced to experimental animals and those available in more complex, chronic and progressive disorders involving patients. (c) Inadequate delivery of the active product to the target area in the human brain. (d) Poor information from acute experiments in animals which does not predict long-term effects of chronic infusion in humans. Further experimental work, therefore, is needed to transfer these neurotrophic factors to the clinic. [ABSTRACT FROM AUTHOR]

The clinical failure rate for disease-modifying treatments (DMTs) that slow or stop disease progression has been nearly 100% for the major neurodegenerative disorders (NDDs), with many compounds failing in expensive and time-consuming phase 2 and 3 trials for lack of efficacy. Here, we critically review the use of pharmacological and mechanistic biomarkers in early phase clinical trials of DMTs in NDDs, and propose a roadmap for providing early proof-of-concept to increase R&D productivity in this field of high unmet medical need. A literature search was performed on published early phase clinical trials aimed at the evaluation of NDD DMT compounds using MESH terms in PubMed. Publications were selected that reported an early phase clinical trial with NDD DMT compounds between 2010 and November 2020. Attention was given to the reported use of pharmacodynamic (mechanistic and physiological response) biomarkers. A total of 121 early phase clinical trials were identified, of which 89 trials (74%) incorporated one or multiple pharmacodynamic biomarkers. However, only 65 trials (54%) used mechanistic (target occupancy or activation) biomarkers to demonstrate target engagement in humans. The most important categories of early phase mechanistic and response biomarkers are discussed and a roadmap for incorporation of a robust biomarker strategy for early phase NDD DMT clinical trials is proposed. As our understanding of NDDs is improving, there is a rise in potentially disease-modifying treatments being brought to the clinic. Further increasing the rational use of mechanistic biomarkers in early phase trials for these (targeted) therapies can increase R&D productivity with a quick win/fast fail approach in an area that has seen a nearly 100% failure rate to date. [ABSTRACT FROM AUTHOR]