Table 1.

MCS-associated genes mutated in ALS.

Locus	Gene	Protein	Protein Function	Role in ALS
21q22.1	SOD1	Superoxide dismutase-1 (SOD1)	UPR activation ERAD inhibition Antioxidant defense Autophagy enhancement	Mutants cause toxic SOD1 clusters aggregation within astrocytes or motor neurons.
2q33.2	ALS2	Alsin	A guanine-nucleotide exchange factor (GEF) to activate the GTPase Rab5.	Mutants influence the functions of endosomes in the subsynaptic reticulum.
9p13-p12	VCP	Valosin-containing protein (VCP) or Transitional endoplasmic reticulum ATPase (TER ATPase)	Ubiquitin/protein degradation Secretory protein trafficking	Mutants disrupt the control of OXPHOS and reduce autophagic clearance of TDP-43 and FUS aggregates.
10p13	OPTN	Optineurin	Selective autophagic adaptor Protein aggregates clearance	Mutants (e.g., E478G, R96L) are associated with both fALS and sALS.
20q13.3	VAPB	Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB)	Vesicle trafficking ATF6 sensor interaction and XBP1 inhibition Lipid metabolism Microtubule organization	A dominantly inherited mutant, P56S-VAPB, causes fALS.
9p13.3	SIGMAR1	Sigma-1 receptor (SIGMAR1)	Calcium signaling Lipid metabolism	A missense mutation in SIGMAR1 (e.g., G304C) causes fALS; Lack of SIGMAR1 induces motoneuron hyperexcitability and exacerabates ALS pathology.
16p11.2	FUS	Fused in sarcoma (FUS)	Transcriptional activation Protein and RNA binding	Mutations in FUS cause fALS and lead to the cytosolic deposition of FUS in the brain and spinal cord of ALS-FUS patients.
1p36.2	TARDBP	TAR-DNA binding protein (TDP43)	Transcriptional repression DNA and RNA binding	TARDBP gene rearrangement has been implicated in the pathogenesis of ALS; Mutations in the TARDBP gene (e.g., M337V and Q331K) are related to ALS.
22q11.23	CHCHD10	Coiled-coil-helix-coiled-coil domain protein 10 (CHCHD10)	Mitochondrial Cristae morphology maintenance Oxidative phosphorylation	Mutants are associated with ALS as well as in other mitochondrial diseases.
17q25	P4HB	Protein disulfide-isomerase A1 (PDIA1)	Disulfide bonds formation, breakage and rearrangement Inhibition of misfolded proteins aggregation	Together with other ER stress markers, PDIA1 is greatly elevated in ALS spinal cord.