Table 1 ALS-FTD genes and their disease mutations linked to autophagy

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. [48,49,50,51]

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. [139,140,141,142,143]

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]