scholarly journals The roles of intrinsic disorder-based liquid-liquid phase transitions in the “Dr. Jekyll–Mr. Hyde” behavior of proteins involved in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Autophagy ◽  
2017 ◽  
Vol 13 (12) ◽  
pp. 2115-2162 ◽  
Author(s):  
Vladimir N. Uversky
GeroScience ◽  
2021 ◽  
Author(s):  
Randall J. Eck ◽  
Brian C. Kraemer ◽  
Nicole F. Liachko

AbstractInsoluble inclusions of phosphorylated TDP-43 occur in disease-affected neurons of most patients with amyotrophic lateral sclerosis (ALS) and about half of patients with frontotemporal lobar degeneration (FTLD-TDP). Phosphorylated TDP-43 potentiates a number of neurotoxic effects including reduced liquid–liquid phase separation dynamicity, changes in splicing, cytoplasmic mislocalization, and aggregation. Accumulating evidence suggests a balance of kinase and phosphatase activities control TDP-43 phosphorylation. Dysregulation of these processes may lead to an increase in phosphorylated TDP-43, ultimately contributing to neurotoxicity and neurodegeneration in disease. Here we summarize the evolving understanding of major regulators of TDP-43 phosphorylation as well as downstream consequences of their activities. Interventions restoring kinase and phosphatase balance may be a generalizable therapeutic strategy for all TDP-43 proteinopathies including ALS and FTLD-TDP.


Polymers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 990 ◽  
Author(s):  
April L. Darling ◽  
Boris Y. Zaslavsky ◽  
Vladimir N. Uversky

The visible outcome of liquid-liquid phase transitions (LLPTs) in cells is the formation and disintegration of various proteinaceous membrane-less organelles (PMLOs). Although LLPTs and related PMLOs have been observed in living cells for over 200 years, the physiological functions of these transitions (also known as liquid-liquid phase separation, LLPS) are just starting to be understood. While unveiling the functionality of these transitions is important, they have come into light more recently due to the association of abnormal LLPTs with various pathological conditions. In fact, several maladies, such as various cancers, different neurodegenerative diseases, and cardiovascular diseases, are known to be associated with either aberrant LLPTs or some pathological transformations within the resultant PMLOs. Here, we will highlight both the physiological functions of cellular liquid-liquid phase transitions as well as the pathological consequences produced through both dysregulated biogenesis of PMLOs and the loss of their dynamics. We will also discuss the potential downstream toxic effects of proteins that are involved in pathological formations.


Brain ◽  
2011 ◽  
Vol 134 (9) ◽  
pp. 2610-2626 ◽  
Author(s):  
Vivek Swarup ◽  
Daniel Phaneuf ◽  
Christine Bareil ◽  
Janice Robertson ◽  
Guy A. Rouleau ◽  
...  

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