Table 1 Overview of defective autophagy in lysosomal storage disorders

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]
Gaucher disease	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.