![]() We did not observe an association between patients with ALS and the rs11701 polymorphism, as previously reported in certain ALS populations of other ethnic origins. Results We observed a previously identified mutation (pI46V) in 2 patients with ALS without a known family link and found a novel mutation (pR121H) in 1 patient who developed ALS with rapid progression. Main Outcome Measures Results of genetic analyses. Patients A total of 855 patients with sporadic ALS. The clinical characteristics of patients carrying ANG mutations are detailed. Fus protein scaffold and client full#Design We analyzed by direct sequencing the full coding region of the ANG gene in a cohort of French patients with sporadic ALS. Objective To assess the frequency of ANG gene mutations in 855 French patients with sporadic ALS. However, the cellular and molecular mechanisms that link ANG, a multidomain protein, to ALS are still unknown. In this review, we discuss how mutations associated with FTD/ALS disrupt mitochondrial function, and we review how the use of Drosophila models has been pivotal to our current knowledge in this field.read more read lessĪbstract: Background Mutations in the angiogenin gene, ANG, have been associated recently with familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Fly models have been often instrumental in understanding the role of disease associated mutations in mitochondria biology. A wide array of fly models have been developed to elucidate the molecular mechanisms of toxicity for mutations associated with FTD/ALS. Drosophila models have been widely used to study FTD and ALS because of their rapid generation time and extensive set of genetic tools. Recent studies have shown that cells derived from patients’ iPSCs display mitochondrial abnormalities, and similar abnormalities have been observed in a number of animal disease models. Among these overlapping features, mitochondrial dysfunction is associated with both FTD and ALS. Even though these diseases present with distinct sets of symptoms, FTD and ALS are two extremes of the same disease spectrum, as they show considerable overlap in genetic, clinical and neuropathological features. Together, these studies strengthen evidence that astrocytes contribute to disease in ALS, establish that FUS-ALS astrocytes induce pathogenic changes to motor neurons in vivo, and provide insights identifying FUS-ALS specific potential therapeutic targets.read more read lessĪbstract: Frontotemporal Dementia (FTD) and Amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterised by declining motor and cognitive functions. We further demonstrate a lack of phenotype in TNF knockout animals expressing mtFUS, and prevention of neurodegeneration in mtFUS-transduced animals through administration of TNF neutralizing antibodies. We show that mtFUS expression causes TNF upregulation, motor function deficits, and spinal motor neuron loss. Here, we developed an intraspinal cord injection model to test whether astrocyte-specific expression of ALS-causative FUSR521G variant (mtFUS) causes neuronal damage in vivo. Previously, we demonstrated that mutations in DNA/RNA binding protein Fused in Sarcoma (FUS) induce neurotoxic phenotypes in astrocytes in vitro, via activation of the NF-B pathway and release of pro-inflammatory cytokine TNF. ![]() Fus protein scaffold and client driver#In addition to direct defects within motor neurons, growing evidence suggests that dysfunction of non-neuronal cells is also an important driver of disease. Abstract: Genetic mutations that cause Amyotrophic Lateral Sclerosis (ALS), a progressively lethal motor neuron disease, are commonly found in ubiquitously expressed genes. ![]()
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