Dysregulation of the Autophagy-Endolysosomal System in Amyotrophic Lateral Sclerosis and Related Motor Neuron Diseases

Table 1

Genes associated with ALS and other neurodegenerative diseases.

Disease type	Locus	Gene	Protein	Inheritance^*	Onset	Function	Mutation linked to other diseases
ALS1	21q22.11	SOD1	SOD1	D	Adult	Oxidative and ER stress response
ALS2	2q33.1	ALS2	ALS2/alsin	R	Juvenile	Trafficking and protein degradation	PLSJ, IAHSP
ALS3	18q21	—	—	D	Adult	—
ALS4	9q34.13	SETX	Senataxin	D	Juvenile	DNA damage response	AOA2
ALS5	15q21.1	SPG11	Spatacsin	R	Juvenile	—	SPG11
ALS6	16p11.2	FUS	FUS	D	Adult	DNA and RNA metabolism	ALS-FTD
ALS7	20p13	—	—	D	Adult	—
ALS8	20q13.32	VAPB	VAPB	D	Adult	ER and Golgi membrane trafficking	SMA4
ALS9	14q11.2	ANG	Angiogenin	D	Adult	Neuroprotection	PD or ALS-PD
ALS10	1p36.22	TARDBP	TDP-43	D, R, or S	Adult	DNA and RNA metabolism	ALS-FTD, FTD
ALS11	6q21	FIG4	FIG4	D or S	Adult	PI (3,5) P2 regulation	CMT4J
ALS12	10p13	OPTN	Optineurin	D or R	Adult	NFkB regulation	GLC1E
ALS13	12q24.12	ATXN2	Ataxin-2	D	Adult	Gene regulation	SCA2
ALS14	9p13.3-p12	VCP	VCP or p97	D	Adult	Protein degradation	IBMPFD
ALS15	Xp11.21	UNQLN2	Ubiquilin-2	D	Adult	Protein degradation	ALS-FTD
ALS16	9p13.3	SIGMAR1	SIGMAR1	R	Juvenile	ER chaperon
ALS-FTD1	9q21-q22	—	—	D or S	Adult	—
ALS-FTD2	9p21.2	C9orf72	C9ORF72	D or S	Adult	—	FTD
ALS-FTD3	3p11.2	CHMP2B	CHMP2B	D	Adult	Trafficking and protein degradation
DHN-7B	2p13.1	DCTN1	Dynactin-1	D	Adult	Trafficking	Perry syndrome
CMT2B	3q21.3	RAB7	Rab7	D	Adult	Trafficking and protein degradation
CMT2O	14q32.31	DYNC1H1	Dynein	D	Adult	Trafficking	SMA-LED and MRD13
ALS^**	5q35.3	SQSTM1	Sequestosome or p62	?	Adult	Protein degradation	PDB

^*Inheritance (D: dominant, R: recessive, and S: sporadic). FTD: Frontotemporal dementia, DHN: distal hereditary motor neuronopathy, CMT: Charcot-Marie-Tooth disease, PDB: Paget disease of bone, PLSJ: primary lateral sclerosis juvenile, IAHSP: infantile-onset ascending hereditary spastic paralysis, AOA: ataxia-ocular apraxia-2, SPG: spastic paraplegia, SMA: spinal muscular atrophy, PD: Parkinson's disease, GLC1E: glaucoma 1, open angle, E, SCA2: spinocerebellar ataxia-2, IBMPFD: inclusion body myopathy with dementia and Paget disease of bone, SMA-LED: spinal muscular atrophy with lower limb predominance, and MRD13: mental retardation, autosomal dominant 13. ^**ALS: Fecoto et al. reported several novel SQSTM1 mutations in patients with ALS and predicted 8 of 9 missense variants behave like a pathogenic mutant by in silico analysis [64].