Table 1.

The association between ALS genes and autophagy.

Gene	Protein	Function	Effect on Autophagy	Reference
SOD1	Superoxide dismutase 1	Antioxidant enzyme: convert superoxide radical anions to oxygen/hydrogen peroxide.	Mutant associates with Beclin1–B cell lymphoma 2 (Bcl2) complex to disrupt the activity of Beclin1 → impairing autophagosome formation/expansion.	[121]
			Mutant and misfolded wild-type sequesters dynein proteins into inclusions → impairing retrograde transport and autolysosome formation.	[90,119,120]
			Mutant binds voltage-dependent anion-selective channel protein 1 (VDAC1) and Bcl2 → impairing mitophagy.	[114,115,116,117,118]
			Mutant binds to optineurin → impairing mitophagy.	[113]
C9ORF72	Chromosome 9 opening reading frame 72	Guanine nucleotide exchange factor (GEFs) for Rab GTPases—allows trafficking via actin, regulates lysosome biogenesis and maturation.	Deficiency disrupts ULK1 complex trafficking → impairing autophagosome formation.	[120]
			Deficiency disrupts transfer of lysosomal proteins to lysosomes → impairing autolysosome formation.	[142]
			Deficiency disrupts its association with early endosomes for lysosome maturation → impairing autolysosome formation.	[142]
FUS	Fused in sarcoma	RNA-binding protein—regulates RNA splicing, processing, transport, and translation.	Mutant disrupts ER–Golgi transport and ER–mitochondrial interactions → impairing autophagosome formation.	[143,144]
			Deficiency decreases Parkin → impairing mitophagy.	[145,146]
TDP-43	TAR DNA binding partner 43	RNA-binding protein—regulates RNA splicing, processing, transport, and translation.	Mutant disrupts ER–Golgi transport and ER–mitochondrial interactions → impairing autophagosome formation.	[143,144]
			Deficiency decreases Parkin → impairing mitophagy.	[145,146]
			Deficiency destabilises Atg7 mRNA and proteins → impairing autophagosome expansion.	[147]
			Mutant inhibits dynactin and HDAC6 → impairing retrograde transport for autolysosome formation.	[148,149]
SQSTM1	Sequestosome 1/p62	Autophagy receptor—recruit cargo to autophagy.	Mutant disrupts recognition of ubiquitinated cargo and their delivery to autophagosomes → impairing cargo degradation.	[120]
OPTN	Optineurin	Autophagy receptor—recruits cargo to autophagy.	Mutant disrupts recognition of ubiquitinated cargo/mitochondria and their delivery to autophagosomes → impairing cargo degradation and mitophagy.	[120]
			Deficiency disrupts its interaction with myosin VI → impairing retrograde transport for autolysosome formation.	[120]
TBK1	Tank-binding kinase 1	Autophagy receptor activator—phosphorylates p62, OPTN, etc. for selective autophagy.	Mutant disrupts its kinase activity of autophagy receptors → impairing cargo/mitochondria degradation.	[150,151]
			Mutant disrupts its kinase activity of microtubule-binding proteins → impairing retrograde transport for autolysosome formation.	[120]
VAPB and VAPC	VAMP-associated protein B and C	ER proteins—activate endoplasmic reticulum-associated protein degradation (ERAD) and autophagy.	Mutant disrupts its interaction with PTPIP51 to allow ER–mitochondrial contact → impairing autophagosome formation.	[152,153]
UBQLN2	Ubiquilin	ER protein—recognises ubiquitinated misfolded proteins.	Mutant disrupts recognition of ubiquitinated cargo and their delivery to autophagosomes → impairing cargo degradation.	[154,155]
VCP	Valosin-containing protein	ER protein—forms aggresomes and translocates them out of ER for degradation.	Mutant disrupts formation of aggresomes and translocates out of ER → impairing cargo degradation	[120,156]
			Mutant disrupts granulophagy (degradation of stress granules).	[157,158]
			Mutant disrupts its recruitment to damaged mitochondria → impairing mitophagy.	[159,160]
CHMP2B	Charged multivesicular body protein 2 B	Endosomal protein—generates multi-vesicular bodies (MVBs).	Mutant disrupts Rab5 conversion to Rab7 → impairing retrograde transport for autolysosome formation.	[161,162,163]
			Mutant disrupts dissociation of its ESCRT-III complex from the endosomal membrane MVB generation → impairing autophagosome maturation.	[161,162,163]
			Mutant disrupts biogenesis and maintenance of lysosomes → impairing autolysosome formation.	[161,162,163]
ALS2	Alsin	Endosomal protein—generates MVBs.	Mutant disrupts its GEF activity of Rab5 → impairing autophagosome maturation.	[164]
FIG4	Polyphosphoinositide 5-phosphatase	Endosomal protein—generates MVBs.	Mutant disrupts PI3P production → impairing autophagosome maturation.	[165]
TUBA4A	Tubulin alpha 4A	Cytoskeleton protein—allows transport within cells.	Mutant disrupts the dynamic and stability of microtubules → impairing retrograde transport for autolysosome formation.	[120,166,167]
PFN1	Profilin1	Cytoskeleton protein— allows transport within cells.	Mutant disrupts its interaction with actin → impairing retrograde transport for autolysosome formation.	[120,166,167]
DCTN	Dynactin	Cytoskeleton protein—allows transport within cells.	Mutant disrupts its complex formation with dynein to bind to microtubules → impairing retrograde transport for autolysosome formation.	[120,166,167]