Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles.

Heterozygous mutations of the gene encoding the postsynaptic protein SHANK3 are associated with syndromic forms of autism spectrum disorders (ASDs). One of the earliest clinical symptoms in SHANK3-associated ASD is neonatal skeletal muscle hypotonia. This symptom can be critical for the early diagnosis of affected children; however, the mechanism mediating hypotonia in ASD is not completely understood.

FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis.

Neuromuscular junction (NMJ) disruption is an early pathogenic event in amyotrophic lateral sclerosis (ALS). Yet, direct links between NMJ pathways and ALS-associated genes such as FUS, whose heterozygous mutations cause aggressive forms of ALS, remain elusive. In a knock-in Fus-ALS mouse model, we identified postsynaptic NMJ defects in newborn homozygous mutants that were attributable to mutant FUS toxicity in skeletal muscle.

Synaptic FUS Localization During Motoneuron Development and Its Accumulation in Human ALS Synapses.

Mutations in the fused in Sarcoma () gene induce cytoplasmic FUS aggregations, contributing to the neurodegenerative disease amyotrophic lateral sclerosis (ALS) in certain cases. While FUS is mainly a nuclear protein involved in transcriptional processes with limited cytoplasmic functions, it shows an additional somatodendritic localization in neurons. In this study we analyzed the localization of FUS in motoneuron synapses, these being the most affected neurons in ALS, using super-resolution microscopy to distinguish between the pre- and postsynaptic compartments.

Retinoic acid worsens ATG10-dependent autophagy impairment in TBK1-mutant hiPSC-derived motoneurons through SQSTM1/p62 accumulation.

Mutations in the (TANK binding kinase 1) gene are causally linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TBK1 phosphorylates the cargo receptors OPTN and SQSTM1 regulating a critical step in macroautophagy/autophagy. Disruption of the autophagic flux leads to accumulation of cytosolic protein aggregates, which are a hallmark of ALS.

NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons.

Mutations in genes coding for proteins involved in DNA damage response (DDR) and repair, such as C9orf72 and FUS (Fused in Sarcoma), are associated with neurodegenerative diseases and lead to amyotrophic lateral sclerosis (ALS). Heterozygous loss-of-function mutations in NEK1 (NIMA-related kinase 1) have also been recently found to cause ALS. NEK1 codes for a multifunctional protein, crucially involved in mitotic checkpoint control and DDR.