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Fig. 1 | Molecular Neurodegeneration

Fig. 1

From: Is amyotrophic lateral sclerosis/frontotemporal dementia an autophagy disease?

Fig. 1

Interactions of ALS/FTD associated genes with autophagy pathway. Several ALS/FTD genes take part in the selective autophagy pathway, which controls the clearance of ubiquitinated proteins and damaged organelles. Autophagy kinase TBK1 phosphorylates two known autophagy receptors p62 and OPTN to facilitate the clearance of ubiquitinated proteins. TBK1 also phosphorylates SMCR8 to regulate the formation of SMCR8, WDR41 and C9ORF72 complex, which acts as a GEF (GDP/GTP exchange factor) for RAB8a/13b, which is associated with the dynamics of autophagosomes. The C9ORF72 complex potentially regulates the ULK1 kinase activity. C9ORF72 can interact with Rab1a and ULK1 complex to regulate autophagy initiation. Moreover, C9ORF72 can negatively regulate autophagy by increasing mTORC1 activity. TDP-43 regulates mTORC1 activity; however, it can enhance autophagosome–lysosome fusion in an mTORC1 independent manner. VAPB, together with PTPIP51, deregulates autophagy flux by controlling the ER-mitochondria contacts. VCP, which cooperates with UBXD1 and YOD1, maintains lysosomal homeostasis. Underlined genes are linked to ALS/FTD. Abbreviations: ALS: Amyotrophic lateral sclerosis; FTD: Frontal-temporal dementia; TDP-43: Transactive response DNA-binding protein 43; SMCR8; Smith-Magenis Chromosome Region gene 8; WDR41: WD repeat domain 41; ULK1: Unc-51 Like Autophagy Activating Kinase 1; C9ORF72: Chromosome 9 open reading frame 72; GEF: Guanine nucleotide exchange factor; mTORC1: mechanistic target of rapamycin complex 1; TBK1: TANK-binding kinase 1; OPTN: Optineurin; LC3: microtubule-associated protein1 light chain 3; VAPB: Vesicle associated membrane protein associated protein B; VCP: Valosin containing protein; SigR1: Sigma receptor-1; UBXD1: ubiquitin regulatory X (UBX) domain-containing protein 1; YOD1: yeast OTU deubiquinating enzyme 1; ER: endoplasmic reticulum; mito: mitochondria; PTPIP51: protein tyrosine phosphatase interacting protein 51.

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