Table 1 Overview of defective autophagy in lysosomal storage disorders
DiseaseGeneProteinFunctionStorage materialAutophagy phenotypeAutophagic fluxMechanism
NEURONAL CEROID LIPOFUSCINOSES
CLN2CLN2/TPP1Tripeptidyl peptidase 1Serine proteaseATPase subunit c, lipofuscinInhibition of autophagosome formation; Reduction in autophagosomes and autophagic degradation [60]InhibitionUp-regulation of mTOR signalling [60]
CLN3CLN3CLN3Unknown function; Lysosomal membrane proteinATPase subunit c, lipofuscinDefect in autophagosome maturation; Accumulation of autophagosomes and autophagic cargo [5860]BlockNot known; Possibly due to alteration in Ca2+ homeostasis [61] and deregulation of ARF1–Cdc42 pathway [62]
CLN5CLN5CLN5Unknown function; Lysosomal proteinATPase subunit c, lipofuscinAccumulation of autophagosomes and autophagic cargo [56]BlockNot known
CLN6CLN6CLN6Unknown function; ER membrane proteinATPase subunit c, lipofuscinAccumulation of autophagosomes and autophagic cargo [55,57]BlockNot known
CLN7CLN7CLN7Putative lysosomal transporterATPase subunit c, lipofuscinAccumulation of autophagosomes and autophagic cargo [56]BlockNot known; Possibly due to impairment in lysosomal function [54]
CLN10CLN10/CTSDCathepsin DAspartyl proteaseATPase subunit c, saposins A/D, lipofuscinAccumulation of autophagosomes and autophagic cargo [64,66]BlockNot known; Possibly due to loss of cathepsin D function [64]
SPHINGOLIPIDOSES
Niemann–Pick type C1NPC1NPC1Cholesterol transporterUnesterified cholesterol, sphingolipidsDefect in autophagosome maturation; Accumulation of autophagosomes and autophagic cargo [7380]BlockDisruption in SNARE machinery [73]; Reduction in sphingosine kinase activity and VEGF [80]
Niemann–Pick type C2NPC2NPC2Putative role in cholesterol metabolism and transportUnesterified cholesterol, sphingolipidsAccumulation of autophagosomes and autophagic cargo [84]BlockNot known; Possibly due to impairment in lysosomal function [84]
Gaucher diseaseGBA1GlucocerebrosidaseSphingolipid degradationGlucosylceramideDefect in autophagosome maturation; Accumulation of autophagosomes and autophagic cargo [91,9397]BlockNot known; Possibly due to down-regulation of TFEB and reduction in lysosomes [91]
PSAPProsaposin, saposin CSphingolipid hydrolase cofactorGlucosylceramideDefect in autophagosome maturation; Accumulation of autophagosomes and autophagic cargo [92,93]BlockNot known; Possibly due to reduction in cathepsin B/D activity [92]
Mucolipidosis type IVMCOLN1TRPML1Late endo-lysosomal Ca2+ transporterGangliosides, phospholipids, mucopolysaccharidesAccumulation of autophagosomes and autophagic cargo [104,105,109]BlockNot known; Possibly due to impairment in lysosomal function [107]
GLYCOGENOSES
Pompe diseaseGAAAcid α-glucosidaseGlycogen degradationGlycogenAccumulation of autophagosomes and autophagic cargo [116118]BlockNot known; Possibly due to defects in lysosomal acidification [116]
Danon diseaseLAMP2Isoform LAMP2bPutative role in autophagosome–lysosome fusionGlycogenAccumulation of autophagosomes and autophagic cargo [123126]BlockNot known; Possibly due to defects in lysosomal function [124]
X-linked myopathy with excessive autophagyVMA21VMA21Regulates v-ATPaseGlycogenAccumulation of autophagosomes [128,129]BlockNot 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.