Disease | Gene | Protein | Function | Storage material | Autophagy phenotype | Autophagic flux | Mechanism |
---|---|---|---|---|---|---|---|
NEURONAL CEROID LIPOFUSCINOSES | |||||||
CLN2 | CLN2/TPP1 | Tripeptidyl peptidase 1 | Serine protease | ATPase subunit c, lipofuscin | Inhibition of autophagosome formation; Reduction in autophagosomes and autophagic degradation [60] | Inhibition | Up-regulation of mTOR signalling [60] |
CLN3 | CLN3 | CLN3 | Unknown function; Lysosomal membrane protein | ATPase subunit c, lipofuscin | Defect in autophagosome maturation; Accumulation of autophagosomes and autophagic cargo [58–60] | Block | Not known; Possibly due to alteration in Ca2+ homeostasis [61] and deregulation of ARF1–Cdc42 pathway [62] |
CLN5 | CLN5 | CLN5 | Unknown function; Lysosomal protein | ATPase subunit c, lipofuscin | Accumulation of autophagosomes and autophagic cargo [56] | Block | Not known |
CLN6 | CLN6 | CLN6 | Unknown function; ER membrane protein | ATPase subunit c, lipofuscin | Accumulation of autophagosomes and autophagic cargo [55,57] | Block | Not known |
CLN7 | CLN7 | CLN7 | Putative lysosomal transporter | ATPase subunit c, lipofuscin | Accumulation of autophagosomes and autophagic cargo [56] | Block | Not known; Possibly due to impairment in lysosomal function [54] |
CLN10 | CLN10/CTSD | Cathepsin D | Aspartyl protease | ATPase subunit c, saposins A/D, lipofuscin | Accumulation of autophagosomes and autophagic cargo [64,66] | Block | Not known; Possibly due to loss of cathepsin D function [64] |
SPHINGOLIPIDOSES | |||||||
Niemann–Pick type C1 | NPC1 | NPC1 | Cholesterol transporter | Unesterified cholesterol, sphingolipids | Defect in autophagosome maturation; Accumulation of autophagosomes and autophagic cargo [73–80] | Block | Disruption in SNARE machinery [73]; Reduction in sphingosine kinase activity and VEGF [80] |
Niemann–Pick type C2 | NPC2 | NPC2 | Putative role in cholesterol metabolism and transport | Unesterified cholesterol, sphingolipids | Accumulation of autophagosomes and autophagic cargo [84] | Block | Not known; Possibly due to impairment in lysosomal function [84] |
Gaucher disease | GBA1 | Glucocerebrosidase | Sphingolipid degradation | Glucosylceramide | Defect in autophagosome maturation; Accumulation of autophagosomes and autophagic cargo [91,93–97] | Block | Not known; Possibly due to down-regulation of TFEB and reduction in lysosomes [91] |
PSAP | Prosaposin, saposin C | Sphingolipid hydrolase cofactor | Glucosylceramide | Defect in autophagosome maturation; Accumulation of autophagosomes and autophagic cargo [92,93] | Block | Not known; Possibly due to reduction in cathepsin B/D activity [92] | |
Mucolipidosis type IV | MCOLN1 | TRPML1 | Late endo-lysosomal Ca2+ transporter | Gangliosides, phospholipids, mucopolysaccharides | Accumulation of autophagosomes and autophagic cargo [104,105,109] | Block | Not known; Possibly due to impairment in lysosomal function [107] |
GLYCOGENOSES | |||||||
Pompe disease | GAA | Acid α-glucosidase | Glycogen degradation | Glycogen | Accumulation of autophagosomes and autophagic cargo [116–118] | Block | Not known; Possibly due to defects in lysosomal acidification [116] |
Danon disease | LAMP2 | Isoform LAMP2b | Putative role in autophagosome–lysosome fusion | Glycogen | Accumulation of autophagosomes and autophagic cargo [123–126] | Block | Not known; Possibly due to defects in lysosomal function [124] |
X-linked myopathy with excessive autophagy | VMA21 | VMA21 | Regulates v-ATPase | Glycogen | Accumulation of autophagosomes [128,129] | Block | Not known; Possibly due to defects in lysosomal acidification and function [128] |
The list in Table 1 highlights selected LSDs where defective autophagy has been demonstrated.