Table 1.

ALS-FTD genes and their disease mutations linked to autophagy

Gene symbol	Protein	Cellular functions	The effect of the genetic variants	Autophagy involvement
C9ORF72	C9orf72	Proteostasis and vesicle dynamics	Loss/gain of function	Regulates initiation of autophagy. [36, 37]
TBK1	TBK1 (TANK-binding kinase 1)	Proteostasis and immunity	Loss of function	Phosphorylates autophagy receptors (p62 and OPTN); regulates selective autophagy. [48–51]
OPTN	Optineurin	Proteostasis, vesicle trafficking and axon homeostasis	Loss of function	A substrate of TBK1 and autophagy receptor protein; selective autophagy. [25, 48, 49]
SQSTM1	p62	Pproteostasis, amino acid sensing, DNA damage response, and oxidative stress	Loss of function	A substrate of TBK1 and ULK1; autophagy receptor; selective autophagy.[25, 50, 68]
UBQLN2	Ubiquilin-2 (UBQLN2)	Proteasome, proteostasis, and vesicle trafficking	Gain/loss of function	A potential autophagy receptor. [88, 89]
TARDBP	TDP-43	RNA regulation	Loss/gain of function	Regulates autophagy initiation and autophagosome-lysosome fusion. [103]
FUS	FUS (fused in sarcoma)	RNA regulation, and DNA damage repair	Loss of function	ALS-linked mutations, P525L and R522G, impair autophagy. [165]
VCP	Valosin-containing protein	ER-associated degradation, DNA damage, and membrane dynamics	Loss of function	Regulates the clearance of lysosomes. [128]
SOD1	Superoxide dismutase 1	Dismutation reaction	Gain of function	Mutant SOD1 disrupts autophagy. [139–143]
ALS2	Alsin	Proteostasis and endosome biogenesis	Loss of function	Pathogenic mutations in ALS2 disrupt the formation of amphisomes. [150]
VAPB	Vesicle-associated membrane protein-associated protein B/C	Proteostasis, calcium homeostasis, and proteins trafficking	Loss of function	Regulates ER-mitochondrial contact. [155]
SigR1	Sigma receptor-1	Proteostasis, Ca2+ signaling, ion channel activity, synaptic plasticity.	Loss of function	Regulates autophagosome-lysosome fusion. [162, 163]