Emerging drug targets in amyotrophic lateral sclerosis

Figures & data

Table 1. Genes associated with FALS.

ALS subtype	Gene	Chromosome region	% of FALS cases	Alternative phenotype	Function
ALS1	SOD1	21q22.1	20	None	Oxidative stress
ALS2	Alsin	2q33	Rare	Spastic paraplegia	Vesicle trafficking
ALS3	Unknown	18q21	Rare	Unknown	Unknown
ALS4	SETX	9q34	Rare	AOA2	RNA processing
ALS5	Unknown	15q15-21.1	Rare	Unknown	Unknown
ALS6	FUS/TLS	16q12	4	FTD	RNA processing
ALS7	Unknown	20p13	Rare	Unknown	Unknown
ALS8	VAPB	20q13.33	Rare	SMD	Vesicle trafficking
ALS9	ANG	14q11	Rare	FTD	RNA processing
ALS10	TDP-43	1p36.22	5	FTD/FTLD-U	RNA processing
ALS11	FIG4	6q21	Rare	Unknown	Vesicle trafficking
ALS12	OPTN	10p15-p14	Rare	Unknown	Vesicle trafficking
ALS13	ATXN2	12q24.12	Rare	Unknown	RNA processing
ALS14	VCP	9p13.3	Rare	IBMPFD	Vesicle trafficking/UPS
ALS15	UBQLN2	Xp11.21	Rare	Unknown	UPS/Autophagy
Undesignated	DAO	12q24	Rare	Unknown	Glutamate transmission
Undesignated	DCTN1	2p13	Rare	FTD	Vesicle trafficking
Undesignated	C9Orf72	9p21	23 – 40	FTD	RNA processing?
Undesignated	PFN1	17p13.3	Rare	Unknown	Actin dynamics

ALS: Amyotrophic lateral sclerosis; ANG: Angiogenin; AOA2: Ataxia with oculomotor apraxia 2; ATXN2: Ataxin-2; DAO: D-amino oxidase; DCTN1: Dynactin 1; FIG4: Factor induced gene 4; FTD: Frontotemporal dementia; FUS/TLS: Fused in sarcoma, translocated in liposarcoma; IBMPFD: Inclusion body myopathy, Paget's disease and frontotemporal dementia; OPTN: Optineurin; PFN1: Profillin 1; SETX: Sentaxin; SMD: Spinal muscular dystrophy; SOD1: Superoxide dismutase; TDP-43: TAR DNA binding protein; UBQLN2: Ubiquilin-2; VAPB: Vesicle-associated membrane protein-associated protein B; VCP: Valosin containing protein.

Figure 1. Hypothetical scheme for activation of ASK1 by oxidative stress. In resting conditions, ASK1 is bound to and negatively regulated by TRX. Under conditions of oxidative stress, TRX becomes oxidized and dissociates from the ASK1 signaling complex (signalosome). DJ-1 becomes oxidized under conditions of oxidative stress (*) and subsequently binds to ASK1, negatively regulating its activity. Continued oxidation of DJ-1 can lead to a conformational change (**) where it dissociates from the ASK1 signalosome, relieving the negative inhibition. ASK1 becomes phosphorylated and is now activated resulting in the activation of JNK and p38 pathways. This schematic connects ASK1, DJ-1 and p38 targets in a common pathway initiated by oxidative stress.