Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease selectively affecting motor neurons, leading to pro-gressive paralysis. Although most cases are sporadic,-10% are familial. Similar protein...Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease selectively affecting motor neurons, leading to pro-gressive paralysis. Although most cases are sporadic,-10% are familial. Similar proteins are found in aggregates in sporadicand familial ALS, and over the last decade, research has been focused on the underlying nature of this common pathology.Notably, TDP-43 inclusions are found in almost all ALS patients, while Fus inclusions have been reported in some familial ALSpatients. Both TDP-43 and FUS possess ‘low-complexity domains' (LCDs) and are considered as ‘intrinsically disordered proteins',which form liquid droplets in vitro due to the weak interactions caused by the LCDs. Dysfunctional ‘liquid-lquid phase separa-tion'(LLPS) emerged as a new mechanism linking AlS-related proteins to pathogenesis. Here, we review the current state ofknowledge on ALS-related gene products associated with a proteinopathy and discuss their status as lLPS proteins. n addition,we highlight the therapeutic potential of targeting LLPS for treating ALS.展开更多
基金Research of the authors is supported by VIB,KU Leuven(Cl and‘Opening the Future’Fund),the‘Fund for Scientific Research Flanders'(FWO-Vlaandere n),the Agency for Irmovation by Science and Technology in Flanders,the Thierry Latran Foundation,the*Association Beige contre les Maladies n euro-Musculaires,(AB MM),the Muscular Dystrophy Association(MDA),Target ALS,the ALS Liga Belgie(A Cure for ALS),and the ALS Association(ALSA).D.P.is funded by the VIB International Life Sciences PhD Program.V.B.is supported by a postdoctoral fellowship from the FWO-Vlaanderen.G.O.ack no wledges funding by the Research Foundation Flan ders(FWO)—project nr.G.0328.16N.
文摘Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease selectively affecting motor neurons, leading to pro-gressive paralysis. Although most cases are sporadic,-10% are familial. Similar proteins are found in aggregates in sporadicand familial ALS, and over the last decade, research has been focused on the underlying nature of this common pathology.Notably, TDP-43 inclusions are found in almost all ALS patients, while Fus inclusions have been reported in some familial ALSpatients. Both TDP-43 and FUS possess ‘low-complexity domains' (LCDs) and are considered as ‘intrinsically disordered proteins',which form liquid droplets in vitro due to the weak interactions caused by the LCDs. Dysfunctional ‘liquid-lquid phase separa-tion'(LLPS) emerged as a new mechanism linking AlS-related proteins to pathogenesis. Here, we review the current state ofknowledge on ALS-related gene products associated with a proteinopathy and discuss their status as lLPS proteins. n addition,we highlight the therapeutic potential of targeting LLPS for treating ALS.
