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Patients with myotonic dystrophy type 1 (DM1) identify chronic fatigue as the most debilitating symptom, which manifests in part as prolonged recovery after exercise. Clinical features of DM1 result from pathogenic gain-of-function activity of transcripts containing an expanded microsatellite CUG repeat (CUGexp). In DM1 mice, therapies targeting the CUGexp transcripts correct the molecular phenotype, reverse myotonia, and improve muscle pathology. However, the effect of targeted molecular therapies on fatigue in DM1 is unknown. Here, we use two mouse models of DM1, age-matched wild-type controls, an exercise-activity assay, electrical impedance myography, and therapeutic antisense oligonucleotides (ASOs) to show that exaggerated exercise-induced fatigue progresses with age, is unrelated to muscle fiber size, and persists despite correction of the molecular phenotype for 3 months. In old DM1 mice, ASO treatment combined with an exercise training regimen consisting of treadmill walking 30 min per day 6 days per week for 3 months reverse all measures of fatigue. Exercise training without ASO therapy improves some measures of fatigue without correction of the molecular pathology. Our results highlight a key limitation of ASO monotherapy for this clinically important feature and support the development of moderate-intensity exercise as an adjuvant for targeted molecular therapies of DM1., Graphical Abstract, DM1 patients cite fatigue as their most debilitating symptom. In old DM1 mice, fatigue is resistant to ASO treatment, despite correction of the molecular phenotype. ASO therapy combined with exercise training reverses all measures of fatigue. This study highlights a key limitation of ASO monotherapy for this clinically important feature.

Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) are ER foldases identified as possible ALS biomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized four ALS‐linked mutations recently identified in two major PDI genes, PDIA1 and PDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of these PDI variants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutant PDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of these PDI mutants. Finally, targeting ERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifies ER proteostasis imbalance as a risk factor for ALS, driving initial stages of the disease.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Disease onset and progression are variable, with survival ranging from months to decades. Factors underlying this variability may represent targets for therapeutic intervention. Here, we have screened a zebrafish model of ALS and identified Epha4, a receptor in the ephrin axonal repellent system, as a modifier of the disease phenotype in fish, rodents and humans. Genetic as well as pharmacological inhibition of Epha4 signaling rescues the mutant SOD1 phenotype in zebrafish and increases survival in mouse and rat models of ALS. Motor neurons that are most vulnerable to degeneration in ALS express higher levels of Epha4, and neuromuscular re-innervation by axotomized motor neurons is inhibited by the presence of Epha4. In humans with ALS, EPHA4 expression inversely correlates with disease onset and survival, and loss-of-function mutations in EPHA4 are associated with long survival. Furthermore, we found that knockdown of Epha4 also rescues the axonopathy induced by expression of mutant TAR DNA-binding protein 43 (TDP-43), another protein causing familial ALS, and the axonopathy induced by knockdown of survival of motor neuron 1, a model for spinomuscular atrophy. This suggests that Epha4 generically modulates the vulnerability of (motor) neurons to axonal degeneration and may represent a new target for therapeutic intervention.

Objetivos. Investigar si los deficits en las funciones ejecutivas en el trastorno por deficit de atencion/hiperactividad (TDAH) afectan a su compresion lectora e identificar un potencial marcador biologico de este endofenotipo neuropsicologico a traves de potenciales relacionados con eventos. Especificamente, hipotetizar si las diferencias en memoria de trabajo e inhibicion mantienen una asociacion fenotipica con la comprension lectora en el TDAH. Sujetos y metodos. La muestra estuvo constituida por 52 ninos con TDAH (8-13 anos) divididos en dos grupos segun la presencia (TDAH–; n = 27; percentil 50) de deficit en compresion lectora y un grupo control (n = 27). Se evaluaron las funciones ejecutivas y se realizo un experimento de potenciales relacionados con eventos en el que se presentaron oraciones anaforicas de diferentes longitudes, y se registraron los potenciales relacionados con eventos en el ultimo adjetivo de la oracion que requiere acuerdo de genero. Resultados. Se encontro una relacion entre memoria de trabajo e inhibicion con el rendimiento en compresion lectora. Mientras que los grupos de TDAH+ y control mostraron signos de deteccion de no concordancia sintactica a los 100 ms, el grupo de TDAH– no activo la memoria de trabajo hasta los 250 ms. Conclusiones. La lentitud en la puesta en marcha de los mecanismos de memoria de trabajo nos ayuda a entender los deficits en comprension lectora del grupo de TDAH–.

Cerebral venous sinus thrombosis (CVST) is not commonly associated with endocrine disorders. However, it has been reported in the setting of ketoacidosis and severe dehydration in children with type 1 diabetes as well as in hyperthyroidism.1,2

Objective: To identify the genetic variant that causes autosomal dominantly inherited motor neuron disease in a 4-generation Israeli-Arab family using genetic linkage and whole exome sequencing. Methods: Genetic linkage analysis was performed in this family using Illumina single nucleotide polymorphism chips. Whole exome sequencing was the nu ndertaken on DNA samples from 2a ffected family members using an Illumina 2000 HiSeq platform in pursuit of potentially pathogenic genetic variants that comigrate with the disease in this pedigree. Variants meeting these criteria were then screened in all affected individuals. Results: A novel mutation (p.R191G) in the valosin-containing protein (VCP) gene was identified in the index family. Direct sequencing of the VCP gene in a panel of DNA from 274 unrelated individuals with familial amyotrophic lateral sclerosis (FALS) revealed 5 additional mutations. Among them, 2 were previously identified in pedigrees with a constellation of inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) and in FALS, and 2 other mutations (p.R159C and p.R155C) in IBMPFD alone. We did not detect VCP gene mutations in DNA from 178 cases of sporadic amyotrophic lateral sclerosis. Conclusions: We report a novel VCP mutation identified in an amyotrophic lateral sclerosis family (p.R191G) with atypical clinical features. In our experience, VCP mutations arise in approximately 1.5% of FALS cases. Our study supports the view that motor neuron disease is part of the clinical spectrum of VCP-associated disease. Neurology � 2012;79:2201–2208

Genetic variants in UBQLN1 gene have been linked to neurodegeneration and mutations in UBQLN2 have recently been identified as a rare cause of amyotrophic lateral sclerosis (ALS). Objective To test if genetic variants in UBQLN1 are involved in ALS. Methods 102 and 94 unrelated patients with familial and sporadic forms of ALS were screened for UBQLN1 gene mutations. Single nucleotide variants were further screened in a larger set of sporadic ALS (SALS) patients and unrelated control subjects using high-throughput Taqman genotyping; variants were further assessed for novelty using the 1000Genomes and NHLBI databases. In vitro studies tested the effect of UBQLN1 variants on the ubiquitin–proteasome system (UPS). Results Only two UBQLN1 coding variants were detected in the familial and sporadic ALS DNA set; one, the missense mutation p.E54D, was identified in a single patient with atypical motor neuron disease consistent with Brown–Vialetto–Van Laere syndrome (BVVLS), for whom c20orf54 mutations had been excluded. Functional studies revealed that UBQLN1 E54D protein forms cytosolic aggregates that contain mislocalized TDP-43 and impairs degradation of ubiquitinated proteins through the proteasome. Conclusions Genetic variants in UBQLN1 are not commonly associated with ALS. A novel UBQLN1 mutation (E45D) detected in a patient with BVVLS altered nuclear TDP-43 localization in vitro , suggesting that UPS dysfunction may also underlie the pathogenesis of this condition.

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years1-9, nearly 50% of FALS cases have unknown genetic etiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is critical for monomeric (G)-actin conversion to filamentous (F)-actin. Exome sequencing of two large ALS families revealed different mutations within the PFN1 gene. Additional sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F-/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by the degeneration of motor neurons and typically results in death within 3–5 years from onset. Familial ALS (FALS) comprises 5%–10% of ALS cases, and the identification of genes associated with FALS is indispensable to elucidating the molecular pathogenesis. We identified a Japanese family affected by late-onset, autosomal-dominant ALS in which mutations in genes known to be associated with FALS were excluded. A whole- genome sequencing and parametric linkage analysis under the assumption of an autosomal-dominant mode of inheritance with incomplete penetrance revealed the mutation c.2780G>A (p. Arg927Gln) in ERBB4. An extensive mutational analysis revealed the same mutation in a Canadian individual with familial ALS and a de novo mutation, c.3823C>T (p. Arg1275Trp), in a Japanese simplex case. These amino acid substitutions involve amino acids highly conserved among species, are predicted as probably damaging, and are located within a tyrosine kinase domain (p. Arg927Gln) or a C-terminal domain (p. Arg1275Trp), both of which mediate essential functions of ErbB4 as a receptor tyrosine kinase. Functional analysis revealed that these mutations led to a reduced autophosphorylation of ErbB4 upon neuregulin-1 (NRG-1) stimulation. Clinical presentations of the individuals with mutations were characterized by the involvement of both upper and lower motor neurons, a lack of obvious cognitive dysfunction, and relatively slow progression. This study indicates that disruption of the neuregulin-ErbB4 pathway is involved in the pathogenesis of ALS and potentially paves the way for the development of innovative therapeutic strategies such using NRGs or their agonists to upregulate ErbB4 functions.