Table 2.

Protein components of paraspeckles (NEAT1 interactors) genetically linked to ALS/FTD.

Protein	Importance for paraspeckle assembly	Regulation of NEAT1_2 levels	Role in ALS	Role in other neurodegenerative diseases
FUS	Essential, >75% loss upon knockdown [37,45]	No or minimal	>50 mutations in fALS and sALS; FUS proteinopathy in these cases [143,144]	FTD (FTLD-FUS) [145]
TDP-43	Depletion enhances paraspeckle assembly [30]	Yes (more NEAT1_2 upon TDP-43 depletion)	>60 mutations in fALS and sALS; TDP-43 proteinopathy in cases with TARDBP and C9ORF72 mutations and in 95% of all sALS cases [110,144,146]	FTD (FTD-TDP) [146]; AD [147]
TAF15	Important, 30–75% loss upon knockdown [37]	No	6 mutations in 6 unrelated sALS cases and 2 mutations – in 2 fALS cases [148,149]	FTD (FTD-FUS) [150]
EWS	Important, 30–75% loss upon knockdown [37]	Yes	2 mutations in 2 unrelated sALS cases [151]	FTD (FTD-FUS) [150]
hnRNPA1	Important, 30–75% loss upon knockdown [37]	No	2 mutations in fALS cases; 2 rare variants [152,153]	Multisystem proteinopathy (MSP) [152]
CRESTa	ND	ND	4 mutations in 4 unrelated sALS cases [154,155]	N/A
MATR3	Depletion enhances paraspeckle assembly [156]	Yes (more NEAT1_2 upon MATR3 depletion)	∼10 mutations in fALS and sALS cases [157,158]	Initially diagnosed myopathy with vocal cord paralysis, diagnosis changed to ‘ALS’ [159]
SFPQ	Essential, >75% loss upon knockdown [37]	Yes	2 mutations in 2 sALS cases [160]	N/A

^aneurospecific, effect on paraspeckles in stable cell lines could not be tested.