Table 1.
List of genes, associated proteins, and childhood-onset neurodegenerative diseases associated with impaired autophagy, ordered by the likely position of each main defect in the autophagy pathway. Gene and protein names as published in UniProt www.uniprot.org.
| Affected stage of the autophagy pathway | Gene | Protein | Disease |
|---|---|---|---|
| Initiation signals to the ULK1 complex: the mTOR pathway | TSC1, TSC2 | Hamartin, Tuberin | Tuberous Sclerosis |
| Initiation signals to the ULK1 complex: the AMPK pathway | e.g. ND5 | NADH-ubiquinone oxidoreductase chain 5 | Leigh encephalopathy |
| Phagophore nucleation | e.g. ATXN3 | Ataxin-3 | Spinocerebellar ataxia type 3 |
| Early phagophore formation | WDR45 | WD repeat domain phosphoinositide-interacting protein 4 (WIPI4) | Beta-propeller protein-associated neurodegeneration (BPAN, NBIA, SENDA) |
| Early phagophore formation | e.g. C19orf12 | Protein C19orf12 | Neurodegeneration with brain iron accumulation (NBIA) (mitochondrial membrane protein-associated neurodegeneration (MPAN), hereditary spastic paraplegia (SPG43)) |
| Phagophore membrane elongation | ATG5 | Autophagy protein 5 | Hereditary childhood ataxia |
| Phagophore membrane elongation | TECPR2 | Tectonin beta-propeller repeat-containing protein 2 | Hereditary spastic paraplegia (SPG49) |
| Phagophore membrane elongation | AP4S1 | AP-4 complex subunit sigma-1 | Hereditary spastic paraplegia (SPG47, SPG52) |
| Phagophore membrane elongation | WDR45 | WD repeat domain phosphoinositide-interacting protein 4 (WIPI4) | Beta-propeller protein-associated neurodegeneration (BPAN, NBIA, SENDA) |
| Autophagosome formation | EPM2A, EPM2B | Laforin, Malin | Lafora disease |
| Cargo recognition and delivery to degradation | SQSTM1/P62 | Sequestosome-1 | Childhood-onset neurodegeneration |
| Cargo recognition and delivery to degradation | IT15 | Huntingtin | Huntington disease |
| Autophagosome maturation | VPS11 | Vacuolar sorting protein VPS11 | Leucoencephalopathy |
| Autophagosome maturation | SPG11, ZFYVE26 | Spatacsin, Zinc finger FYVE domain-containing protein 26 (spastizin) | Hereditary spastic paraplegia (SPG11, SPG15 (SPG15 also interacts with Beclin1) |
| Autophagosome/lysosome fusion | EPG5 | Ectopic p-granules protein 5 homologue | VICI syndrome |
| Regulation of lysosome function | CCT5 | Chaperonin-containing T-complex protein 1 subunit epsilon | Hereditary spastic paraplegia |
| Regulation of lysosome function | SNX14 | Sorting nexin-14 | Ataxia |
| Lysosomal/autolysosomal acidification | DNM2 | Dynamin 2 | Charcot Marie Tooth disease |
| Transport of autolysosome cargoes | DYNC1H1 | Dynein cytoplasmic 1 heavy chain 1 | Spinal muscular atrophy |