Table 1.

Main alterations in lysosome function and autophagy pathways observed in a subset of rare neurodegenerative diseases

Disease	Mutated gene	Function	Accumulation of material	Autophagy step altered	Secondary cellular dysfunctions, possibly associated to neurodegeneration	References
Primary lysosomal dysfonction
GM1 gangliosidosis	GLB1	β-Galactosidase	GM1	Increased autophagy activation	Impaired mitochondrial function	[4]
Mucolipidosis type II (and type III)	GNPTAB	N-acetylglucosamine-1-phosphotransferase, required for trafficking of lysosomal hydrolases	Mutilamellar bodies, lipofusin, glycans, gangliosides	Accumulation of autolysosomes		[5]
Mucolipidosis type IV	TRPML1	Lysosomal calcium channel		Accumulation of enlarged autolysosomes, accumulation and impaired degradation of autophagosomes	Accumulation of dysfunctional mitochondria	[6,7]
Gaucher disease	GBA1	Glucocerebrosidase	Glucosylceramide, glucosylsphingosine,	Impaired autophagosome–lysosome fusion, decreased autophagic flux, impaired ALR	Accumulation of dysfunctional mitochondria, loss of synapses	[[8], [9], [10]]
Fabry disease	GLA	α-Galactosidase	Globotriaosylceramide (Gb3), lipopigment aggregates, α-synculein	Impaired autophagic flux; impaired ALR		[[11], [12], [13]]
CLN3	CLN3	Unknown	Lipofuscin, subunit c of mitochondrial F0-ATPase	Impaired autophagic flux; impaired autolysosome degradation; impaired autophagosome–lysosome fusion		[14,15]
CLN7	CLN7	Unknown, putative transporter	Lipofuscin, saposinD	Impairment of constitutive macroautophagy, accumulation of p62		[16]
CLN8	CLN8	Endoplasmic protein required for trafficking of lysosomal hydrolases	Lipofuscin, ATP synthase subunit c		ER stress; deficient mitochondrial calcium buffering	[[17], [18], [19], [20], [21]]
CLN10	CTSD	Lysosomal hydrolase cathepsin D	Lipofuscin, accumulation of autolysosomes	Impaired degradation of lysosome content		[22,23]
CLN11	PGRN (loss of function)	Protein processed into granulin peptides	Lipofuscin deposit, TDP43	Impaired clearance of autophagosomes	Decreased levels of saposin and decreased activity of cathepsin D	[[24], [25], [26], [27]]
FTLD-GRN	PGRN (haploinsufficiency)	Protein processed into granulin peptides	TDP43, lipofuscin	Impaired clearance of autophagosomes	Decreased levels of saposin and decreased activity of cathepsin D	[[24], [25], [26], [27]]
CLN12 Parkinson's disease (PARK9) HSP (SPG78)	ATP13A2	P5ATPase	Lipofuscin	Impaired lysosomal degradative activity, impaired autophagosome–lysosome fusion, accumulation of autolysosomes	Impaired lysosome acidification, accumulation of impaired mitochondria	[28,29]
X-linked parkinsonism with spasticity	ATP6AP2	Accessory protein of vATPase, required for lysosome acidification	Accumulation of electron dense material detected by electron microscopy	Accumulation of autophagy substrates	Abnormal synaptic function, impaired myelination	[30,31]
NPC	NPC1 NPC2	Cholesterol transport	Cholesterol, glycosphingolipids	Impaired autophagosome–lysosome fusion; impaired clearance of autophagosomes	Accumulation of mitochondria, oxidative stress	[[32], [33], [34], [35], [36], [37]]
Cargo recognition
FTDALS3	SQSTM1	Autophagy receptor p62	Ubiquitin, p62, TDP-43	Decreased clearance of protein aggregates	Impaired mitochondrial respiration	[[38], [39], [40]]
ALS15 FTLD	Ubiquilin-2	Autophagy receptor	Poly-ubiquitinated proteins, TDP43	Decreased clearance of poly-ubiquitinated proteins	Toxic gain of function? Impaired acidification of lysosomes?	[[41], [42], [43], [44]]
ALS12 FTLD	OPTN	Autophagy receptor	TDP43	Decreased clearance of protein aggregates, pathogens, and mitochondria	Accumulation of defective mitochondria	[45,46]
FTDALS4	TBK1	Kinase regulating autophagy receptors	TDP-43	Impaired phosphorylation of autophagy receptors, decreasing their activities	Impaired mitophagy	[[45], [46], [47], [48]]
Huntington disease	HTT	Huntingtin	Aggregation of mutant huntingtin	impaired cargo recognition mediated by mutant huntingtin		[49,50]
Autophagosome formation
SCA25 (autosomal recessive ataxia)	ATG5 (missense)	Conjugation of LC3 to PE		Decreased interaction with ATG12, decreased autophagosome formation		[51]
Neurodegeneration with brain iron accumulation	WDR45	Interacts with ATG2 and ATG9	Accumulation of autophagosomes and immature autophagic vesicles	Impaired autophagosome formation and elongation	Impaired iron homeostasis ?	[52,53]
HSP (SPG49)	TECPR2	Maintenance of ER exit sites, interaction with LC3		Impaired autophagosome formation		[54,55]
HSP (SPG47, SPG50, SPG51, SPG52); AP4 syndrome	AP4S1, AP4M1, AP4B1, AP4E1	Adaptor protein complex-4	Brain iron accumulation detected by MRI	Accumulation of ATG9 in trans-Golgi, impaired autophagosome formation?		[[56], [57], [58], [59]]
FTDALS1	C9ORF72	Guanine nucleotide exchange factor?	TDP-43, Lipid accumulation in lysosomes	Decreased autophagosome formation; Increased autophagic flux		[[60], [61], [62]]
ALS10 FTLD	TARDBP	RNA regulation	TDP-43	Decreased or increased autophagosome formation?		[63,64]
ALS6 FTLD	FUS	RNA regulation	FUS	Decreased omegasome formation		[65]
ALS1	SOD1	Superoxide dismutase	SOD1	Increased induction of autophagy		[66,67]
Spinocerebellar ataxia SCA3	SCA3	Ataxin3	Ataxin3 with poly-glutamine expansions, positive for p62 and ubiquitin	Impaired autophagosome formation		[68,69]
Spinocerebellar ataxia SCA7	SCA7	Ataxin7	Ataxin7 with poly-glutamine expansions; aggregates positive for mTOR, Beclin, p62, and ubiquitin	Impaired autophagosome formation? Impaired autophagic flux		[70]
Huntington disease	HTT	Huntingtin	Aggregation of mutant huntingtin	Impaired activation of autophagy or autophagosome formation		[49,50,68]
Autophagosome–lysosome fusion and autolysosome clearance
Huntington disease	HTT	Huntingtin	Aggregation of mutant huntingtin	Impaired autophagosome trafficking leading to impaired fusion with lysosomes		[71]
ALS1	SOD1	Superoxide dismutase	SOD1	Impaired retrograde transport of autophagosomes, preventing fusion with lysosomes	Accumulation of dysfunctional mitochondria	[72]
ALS2	ALS2	Alsin, guanine nucleotide exchange factor for the small GTPase Rab5		Impaired autophagosome clearance		[73]
ALS10 FTLD	TARDBP	RNA regulation	TDP-43	Impaired autophagosome–lysosome fusion		[64]
ALS14 FTLD Inclusion body myopathy	VCP	Valosin containing protein; AAA-ATPase	TDP43, ubiquitin positive inclusions	Accumulation of damaged lysosomes, impaired autophagosome–lysosome fusion		[[74], [75], [76]]
ALS17 FTLD	CHMP2B	Subunit of the endosomal sorting complex required for transport (ESCRT-III)	P62-positive inclusions; Lipofuscin-like autofluorescent aggregates	Impaired maturation of phagophore into autophagosome; impaired endosome-lysosome fusion		[77,78]
ALS	DCTN1	Subunit of dynein–dynactin complex	Ubiquitin-, p150Glued-positive inclusions	Impaired autophagosome trafficking, impaired autophagosome–lysosome fusion		[79,80]
Charcot–Marie–Tooth 2B	RAB7 point mutations	Rab GTPase		Reduced fusion of autophagosomes with lysosomes	Impaired signaling, axon growth defects	[81,82]
Vici syndrome	EPG5	Rab7 effector		Impaired autophagosome–lysosome fusion; impaired degradation of autolysosomes		[83,84]
Autosomal recessive ataxia	SNX14	Intracellular membrane trafficking	Lysosomal accumulation of cholesterol	Impaired autophagosome clearance; impaired autophagosome–lysosome fusion?	Impaired lipid metabolism	[85,86]
Dentatorubral-pallidoluysian Atrophy	ATN1	Atrophin		Blockade of autolysosome egradation	Disrupted nuclear organization	[87,88]
Lysosome recycling
HSP (SPG11) ALS5	SPG11	Initiation of ALR	Lipids (cholesterol, gangliosides), lipofucsin-like, autolysosomes	Impaired ALR, accumulation of autolysosomes	Impaired cellular calcium homeostasis	[[89], [90], [91], [92]]
HSP (SPG15)	SGP15	Initiation of ALR	Fingerprint bodies, lipofuscin-like deposits, autolysosomes	Impaired ALR, accumulation of autolysosomes		[92,93]
HSP (SPG48)	SPG48	Adaptor protein complex 5	Membrane swirls, lipofuscin-like deposits, autolysosomes	Accumulation of autophagosomes and autolysosomes, impaired ALR	Alteration of Golgi network	[94]
ALS11 Charcot–Marie–Tooth 4J	FIG4	PI(3,5)P2 phosphatase, subunit if PIKFyve	Accumulation of large lysosomes containing electron dense material in neurons and glia	Impaired lysosomal fission	Impaired lysosomal calcium homeostasis, impaired synapse morphology	[95,96]

ALR, autophagic lysosome reformation.