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Abstract Valosin-containing protein (VCP) is a ubiquitously expressed type II AAA+ ATPase protein, implicated in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study aimed to explore the impact of the disease-causing VCP R191Q/wt mutation on mitochondrial function using a CRISPR/Cas9-engineered neuroblastoma cell line. Mitochondria in these cells are enlarged, with a depolarized mitochondrial membrane potential associated with increased respiration and electron transport chain activity. Our results indicate that mitochondrial hypermetabolism could be caused, at least partially, by increased calcium-induced opening of the permeability transition pore (mPTP), leading to mild mitochondrial uncoupling. In conclusion, our findings reveal a central role of the ALS/FTD gene VCP in maintaining mitochondrial homeostasis and suggest a model of pathogenesis based on progressive alterations in mPTP physiology and mitochondrial energetics.

Summary: RNA-binding protein aggregation is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To gain better insight into the molecular interactions underlying this process, we investigated FUS, which is mutated and aggregated in both ALS and FTLD. We generated a Drosophila model of FUS toxicity and identified a previously unrecognized synergistic effect between the N-terminal prion-like domain and the C-terminal arginine-rich domain to mediate toxicity. Although the prion-like domain is generally considered to mediate aggregation of FUS, we find that arginine residues in the C-terminal low-complexity domain are also required for maturation of FUS in cellular stress granules. These data highlight an important role for arginine-rich domains in the pathology of RNA-binding proteins. : Protein aggregation is a hallmark of ALS. Bogaert et al. describe the molecular interactions between disordered regions of the FUS protein driving its liquid phase behavior, maturation, and neurotoxicity. These findings highlight the physicochemical interactions driving FUS phase separation and give us insights into its misregulation in disease. Keywords: amyotrophic lateral sclerosis, frontotemporal lobar degeneration, phase transition, LLPS, protein aggregation, FUS, prion-like domain, low-complexity domain, intrinsically disordered protein

Both in mice and humans, low expression levels of vascular endothelial growth factor (VEGF) are linked to adult-onset motor neuron disease or amyotrophic lateral sclerosis (ALS). The mechanism through which reduced VEGF levels result in this phenotype is unknown. We therefore examined the direct effects of VEGF on motor neurons and found VEGF to have a direct neurotrophic effect on motor neurons in vitro. Survival and vulnerability to excitotoxicity of motor neurons from VEGFδ/δ mice was however similar to that of motor neurons from non-transgenic littermates. The VEGF concentration in the spinal cord of mutant (G93A) SOD1 mice was not different from that found in wild-type SOD1 overexpressing mice. Upregulation of VEGF in the spinal cord, by housing mutant (G93A) SOD1 mice in hypoxic conditions, did not affect their life span. Our results show that VEGF is a neurotrophic factor for motor neurons in vitro, and shortage of this neurotrophic factor may contribute to the motor neuron death observed in humans and animals with low VEGF expression levels.