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Role and therapeutic potential of liquid–liquid phase separation in amyotrophic lateral sclerosis
Donya Pakravan1,2 , Gabriele Orlando3 , Vale´rie Bercier1,2 , Ludo Van Den Bosch1,2,*
1Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven—University of Leuven, 3000 Leuven, Belgium
2Laboratory of Neurobiology, VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium
3Switch Laboratory, VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium
*Correspondence to:Ludo Van Den Bosch ,
J Mol Cell Biol, Volume 13, Issue 1, January 2021, Pages 15-28
Keyword: phase separation, stress granule, motor neuron, ALS therapy

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease selectively affecting motor neurons, leading to progressive paralysis. Although most cases are sporadic, ∼10% are familial. Similar proteins are found in aggregates in sporadic and 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 ALS patients. 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–liquid phase separation’ (LLPS) emerged as a new mechanism linking ALS-related proteins to pathogenesis. Here, we review the current state of knowledge on ALS-related gene products associated with a proteinopathy and discuss their status as LLPS proteins. In addition, we highlight the therapeutic potential of targeting LLPS for treating ALS.