Figure 1.: Dysfunction of autophagy-related proteins impairs proteostasis and leads to neur...

Dysfunction of autophagy-related proteins impairs proteostasis and leads to neurotoxicity in ALS. ( A ) Under normal conditions, SQSTM1 serves as a receptor protein in selective autophagy and binds both LC3-II and polyubiquitinated proteins, thereby targeting ubiquitinated substrates to phagophores ( left ); Mutations in SQSTM1 abrogate SQSTM1’s binding activities ( right top ) or result in the aggregation of SQSTM1 into ubiquitin-positive inclusions ( right bottom ). ( B ) The C9orf72 protein participates in several autophagy-related complexes, including the autophagy induction complex (ULK1-RAB1A) that promotes autophagosome biogenesis, the RAB7-RAB11 complex ( RAB complex ) that regulates endosome maturation, and the C9orf72-SMCR8-WDR41 (CSW) complex that regulates lysosomal dynamics and autophagic flux ( left ). Disease-associated C9orf72 mutations reduce C9orf72 protein levels ( right ), while dipeptide repeat proteins generated from the C9orf72 expansion localize to SQS

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