Table 1.

Summary of ALS genes involved in autophagy impairment

Gene	Role in Autophagy	References
SOD1	Mutants induce autophagy through undefined mechanisms and interfere with autophagosome maturation by disrupting the microtubule-localized dynein-dynactin complex integral to retrograde transport.	[38–40,44,47,49]
TDP-43	Gains toxicity via the formation of proteinaceous inclusions, known substrates of autophagy. Loss of nuclear functions caused by chronic sequestration in RNP granules results in reduced expression of autophagic factors that function at various events within the autophagy-lysosomal pathway.	[88–90,97–99]
FUS	Gains toxicity via formation of proteinaceous inclusions, known substrates of autophagy. Possible direct disruption of autophagy regulation.	[83,90,93]
P62	Functions as an autophagy receptor. ALS-linked mutations may impede its association with ubiquitinated substrates or block its association with autophagic membranes via LC3-II.	[32,104]
OPTN	Autophagy adaptor that binds ubiquitinated cargo via UBA and LC3 via LIR; also regulates autophagosome formation and maturation.	[124–127]
TBK1	Phosphorylates the UBA domain of autophagy adaptors p62 and OPTN; ALS-associated mutants induce dysfunctions in C-terminal CCD2 and serine/threonine kinase domains that may inhibit p62/OPTN activation; also involved in autophagy initiation via phosphorylation of the C9orf72 binding partner SMCR8; phosphorylation of microtubule-binding protein CEP170 underscores involvement in autophagosome maturation.	[132,134,140–143]
VAPB	ER resident that tethers with mitochondrial protein PTPIP51, regulating autophagosome formation; tightening of the tether represses autophagosome formation, while loosening stimulates formation; modulatory effects in autophagic induction vary depending on autophagic stimuli (chemical vs. starvation-induced); ALS-associated mutations induce oligomerization and aggregation of VAPB that overburdens ERAD, hastening ALS pathology.	[89,149–152]
VCP	Precise roles are uncertain, but speculated to diversely affect autophagy; ALS-associated mutations reduce mTOR activity, aberrantly induce autophagy; mutations also impede autophagosome-autolysosome maturation, and potentially impair autophagic clearance following autophagosome-lysosome fusion; mutants repress TDP-43-containing RNP complex disassembly.	[156,157,163]
C9orf72	A DENN domain protein, suggested to possess multifunctional roles in autophagy initiation, nutrient sensing, and lysosomal pathways.	[137–140,186–189]
UBQLN2	Recruits autophagosomes to polyubiquitinated aggregates via UBA domain interactions; mutants may hinder the endosomal pathway	[128,190,191,240]
ALS2	Functions as GEF of Rab5, mediating endosome trafficking and fusion. Loss-of-function mutations lead to impeded maturation and clearance of autophagic vesicles.	[13,119,205]
CHMP2B	Carries out ESCRT-III dissociation from endosomal membranes, forming MVBs that transition to amphisomes, which fuse with lysosomes; toxic gain-of-function ALS-FTD-associated mutations are C-terminal truncations that disrupt late-stage endosome-lysosome fusion.	[212–214]
DCTN	Involved in retrograde transport of autophagic substrates; ALS-associated mutations exhibit impaired intracellular trafficking, immature autophagosome accumulation, and hastened MN degeneration.	[218–221]
PFN1	Regulates actin dynamics, membrane trafficking, and synaptic structure; ALS-associated gain-of- function mutants may disrupt TDP-43 binding partner interactions, inducing deleterious conformational changes.	[229–231]
FIG4	A required phosphatase for IP(3,5)P2 biosynthesis. Loss of function mutations result in a reduction in IP(3,5)P2 level, subsequently leading to enlarged endosomes and disrupted autolysosome clearance.	[235,236,239]