Table 1:
Mutations in neurodegeneration-related genes that affect macroautophagy
| Gene/ Protein | Neurodegenerative disease | Stage of the autophagy pathway were a protein acts | Cellular phenotype upon mutation or loss of function of a protein |
|---|---|---|---|
| Core macroautophagy | |||
| ATG5/ Autophagy-related 5 | Hereditary childhood ataxia | Early phagophore formation and elongation | Decreased autophagosome formation caused by weak binding of ATG5 to ATG12 (Kim et al., 2016) |
| WIPI2/ WD repeat domain phosphoinositide-interacting protein 2 | Severe cognitive impairment | Early phagophore formation and elongation | Decreased autophagosome formation caused by reduced binding of WIPI2b to ATG16L1, as well as ATG5–12 (Jelani et al., 2019) |
| WDR45/ WD repeat domain phosphoinositide interacting protein 4 (WIPI4) | Beta-propeller protein-associated neurodegeneration (BPAN, NBIA, SENDA) | Early phagophore formation and elongation/ Autophagosome-lysosome fusion | Impairment in autophagy flux and an accumulation of LC3-positive autophagosome membranes (Saitsu et al., 2013) and ubiquitinpositive aggregates (Zhao et al., 2015); impaired formation of fusion machinery (Ji et al., 2021) |
| Other genes that impact autophagy | |||
| ATXN3/ Ataxin-3 | Spinocerebellar ataxia type 3 (SCA3) | Early phagophore formation | Impaired initiation in starvation-induced autophagy (Ashkenazi et al., 2017) |
| GJB1/ gap junction protein connexin 32 | Charcot-Marie-Tooth type 1 (CMT1) | Autophagosome formation | Reduced autophagosome formation (Bejarano et al., 2014) |
| VPS35 / Vacuolar protein sorting-associated protein 35 | Parkinson’s disease (PD) | Autophagosome formation and elongation | Abnormal trafficking of mATG9 and autophagy impairment (Zavodszky et al., 2014) |
| EPM2A, EPM2B/ Laforin, Malin | Lafora disease | Autophagosome formation and elongation | Decreased LC3 lipidation and increase in p62 (Aguado et al., 2010); defective regulation of PI3KC3 complex; decreased PI(3)P levels (Sanchez-Martin et al., 2020) |
| TECPR2 / Tectonin beta-propeller repeat containing 2 TECPR2 | Spastic paraplegia type 49 (SPG49) | Phagophore membrane elongation | Decrease in LC3 lipidation and levels of LC3 and WIPI2 (Oz-Levi et al., 2012; Stadel et al., 2015) |
| AP4S1/ AP-4 complex subunit sigma-1 | Hereditary spastic paraplegia (SPG47, SPG52) | Phagophore membrane elongation | Deficiency causes mis-sorting of mATG9 (Davies et al., 2018) |
| PICALM/ Phosphatidylinositol-Binding Clathrin Assembly Protein | Alzheimer’s disease (AD) | Autophagosome formation/ maturation | Autophagosome formation and maturation dysfunction; impaired APP cargo recognition (Moreau et al., 2014; Tian et al., 2013) |
| C9ORF72 / Hexanucleotide-repeat expansions in a non-coding region of chromosome 9 open reading frame 72 | Amyotrophic lateral sclerosis (ALS); frontotemporal dementia (FTD) | Autophagosome formation/ maturation | Impaired autophagy flux (Farg et al., 2014); impaired trafficking of the ULK1 initiation complex to the phagophore (Webster et al., 2016) |
| SNCA/ α-synuclein | Parkinson’s disease (PD) | Autophagosome formation/ maturation | Impaired autophagosome transport (Tanik et al., 2013; Volpicelli-Daley et al., 2014); abnormal mATG9 trafficking (Winslow et al., 2010); disturbed TFEB-mediated lysosomal biogenesis (Decressac et al., 2013) |
| VCP/ Valosin-containing protein VCP | Inclusion body myopathy with earlyonset Paget disease and frontotemporal dementia (IBMPFD), Amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth type 2 (CMT2), tauopathies | Autophagosome formation / maturation | Loss of ATPase activity causes impaired autophagosome formation (Hill et al., 2021); impaired autophagosome maturation (Ju et al., 2009; Tresse et al., 2010); recruited to damaged lysosomes to facilitate lysophagy (Papadopoulos et al., 2020) |
| SPG11/ spatacsin | Hereditary spastic paraplegia (SPG11) | Autophagosome maturation | Impaired autophagic lysosome reformation (Chang et al., 2014; Vantaggiato et al., 2019) |
| ZFYVE26 / spastizin (SPG15) | Hereditary spastic paraplegia (SPG15) | Autophagosome maturation | Disrupts interaction with Beclin 1 which impairs autophagosome maturation (Vantaggiato et al., 2013) and lysosomal biogenesis (Chang et al., 2014; Vantaggiato et al., 2019) |
| RAB7A / Ras-associated protein Rab-7a | Charcot-Marie-Tooth type 2 (CMT2) | Autophagosome maturation | Impaired autophagosome-lysosome fusion (Ganley et al., 2011) |
| ALS2/ ALSIN | Amyotrophic lateral sclerosis (ALS) | Autophagosome maturation | Impaired autophagosome fusion with endosomes through its regulation of RAB5 (Ravikumar et al., 2008) |
| UBQLN2 / Ubiquilin 2 | Amyotrophic lateral sclerosis (ALS) | Autophagosome formation/ maturation/ Lysosomal function | Impaired autophagosome maturation (N’Diaye et al., 2009); impaired LC3 lipidation (Rothenberg et al., 2010); impaired autophagic flux caused by lysosomal defect (Şentürk et al., 2019; Wu et al., 2020); decrease in the levels of autophagic proteins (Chen et al., 2018) |
| HTT / Huntingtin | Huntington’s disease | Autophagosome formation/ Autophagosome-lysosome fusion/ Cargo recognition | Impaired cargo recognition (Martinez-Vicente et al., 2010; Ochaba et al., 2014; Rui et al., 2015); decreased autophagosome transport (Wong and Holzbaur, 2014b); impaired starvation-induced autophagy initiation (Ashkenazi et al., 2017) |
| CHMP2B/ Charged multivesicular body protein 2b | Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) | Autophagosome-lysosome fusion Required for eMI | Impaired autolysosome formation (Filimonenkoet al., 2007; Lee et al., 2007) |
| MAPT/ microtubule-associated protein tau | Alzheimer’s disease (AD), tauopathies | Autophagosome-lysosome fusion | Dysfunction of the retrograde axonal transport of autophagosomes (Butzlaff et al., 2015; Majid et al., 2014) |
| SNX14/ Sorting nexin-14 | Spinocerebellar Ataxia Type 20 (SCAR20) | Autophagosome-lysosome fusion | Impaired autophagosome clearance (Akizu et al., 2015); impaired lysosomes (Bryant et al., 2018) |
| DCTN1/ Dynactin | Amyotrophic lateral sclerosis (ALS) | Autophagosome-lysosome fusion | Impaired autophagosome-lysosome fusion (Ravikumar et al., 2005) |
| PSEN1/ Presenilin 1 | Alzheimer’s disease (AD) | Lysosomal function | Impaired autophagosome-lysosome fusion and defective lysosomal acidification (Chong et al., 2018; Leeet al., 2010; Zhang et al., 2012) |
| GBA/ Lysosomal acid glucosylceramidase | Parkinson’s disease (PD) | Lysosomal function | Impaired autophagy caused by lysosomal dysfunction (Murphyet al., 2014); impaired removal of dysfunctional mitochondria by mitophagy (Li et al., 2019b) |
| ATP13A2/ Polyaminetransporting ATPase 13A2 | Parkinson’s disease (PD) | Lysosomal function | Impaired lysosome acidification (Bento et al., 2016; Dehay et al., 2012) |
| SYT11/ synaptotagmin 11 | Parkinson’s disease (PD) | Lysosomal function | Lysosomal dysfunction ((Bentoet al., 2016) |
| GRN/ Progranulin | Frontotemporal lobar degeneration (FTLD) | Lysosomal function | Impaired lysosomal function (Logan et al., 2021);deficiency in neurons increases autophagy flux and causes abnormally enlarged lysosomes (Elia et al., 2019) |
| FIG4/ Polyphosphoinositide phosphatase FIG4 | Charcot-Marie-Tooth disease 4J (CMT4J), Amyotrophic lateral sclerosis 11 (ALS11), Yunis-Varon syndrome (YVS) | Lysosomal function | Impaired production of PI(3,5)P(2), impaired endo-lysosomes, accumulation of p62 (Ferguson et al., 2009) |
| VPS13D/ Vacuolar protein sorting 13D | ataxia and/or spastic paraplegia | ? | Accumulation of damaged mitochondria (Anding et al., 2018) |
| PEX13/ Peroxisomal membrane protein PEX13 | Human peroxisome biogenesis disorders (PBDs) | ? | Impaired mitophagy without disruption of general autophagy (Lee et al., 2017) |
| Macroautophagy adaptors | |||
| SQSTM1/ Sequestosome-1 (p62) | Amyotrophic lateral sclerosis (ALS), Frontotemporal lobar degeneration (FTLD) | Cargo recognition | Impaired recruitment into autophagosomes (Goode et al., 2016); impaired cargo recognition and protein clearance (Gal et al., 2009) |
| OPTN/ Optineurin | Amyotrophic lateral sclerosis (ALS) | Cargo recognition/ Autophagosome formation and maturation | Impaired cargo recognition and protein clearance (Shenet al., 2015); impaired ATG5-ATG12-ATG16L recruitment to phagophore and decreased formation (Bansal et al., 2018; Song et al., 2018); impaired autophagosome trafficking to lysosomes (Sundaramoorthy et al., 2015; Tumbarello et al., 2012) |
| TBK1/TANK-binding kinase 1 | Amyotrophic lateral sclerosis (ALS) | Promotes efficient cargo recognition by OPTN and regulates other autophagic proteins | Impaired mitophagy (Moore and Holzbaur, 2016; Pilli et al., 2012; Richteret al., 2016) |
| RETREG1/ Reticulophagy regulator 1 (FAM134B) | Hereditary sensory and autonomic neuropathy type II (HSAN II) | ER-phagy receptor | Impaired ER-phagy though decrease binding to autophagy modifiers LC3 and GABARAP (Bhaskaraet al., 2019; Khaminets et al., 2015) |
| ATL1 and ATL3/ Atlastin 1 and 3 | hereditary spastic paraplegia (HSP), hereditary sensory and autonomic neuropathies (HSAN) | ER-phagy receptor / autophagy initiation at ER | Depletion inhibits ER-phagy, acts downstream of FAM134B during ER-phagy (Liang et al., 2018); impaired association with GABARAP and impaired ER-phagy (Chenet al., 2019); impaired recruitment of ULK1 complex to ER-specific site of autophagosome formation (Liu et al., 2021) |
| PINK1/ Serine/threonine-protein kinase PINK1 | Parkinson’s disease (PD) | Sensor of mitochondrial stress/ Promotes efficient mitophagy | Impaired mitophagy (reviewed in (Ge et al., 2020) |
| PRKN/ E3 ubiquitin-protein ligase PARKIN | Parkinson’s disease (PD) | Amplifies damage mitochondria detection signal/ Promotes efficient mitophagy | Impaired mitophagy (reviewed in(Geet al., 2020) |