Stress Granule Homeostasis, Aberrant Phase Transition, and Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. In recent years, a large number of ALS-related mutations have been discovered to have a strong link to stress granules (SGs). SGs are cytoplasmic ribonucleoprotein condensates mediated by liquid−liquid phase separation (LLPS) of biomacromolecules. They help cells cope with stress. The normal physiological functions of SGs are dependent on three key aspects of SG "homeostasis": SG assembly, disassembly, and SG components. Any of these three aspects can be disrupted, resulting in abnormalities in the cellular stress response and leading to cytotoxicity. Several ALS-related pathogenic mutants have abnormal LLPS abilities that disrupt SG homeostasis, and some of them can even cause aberrant phase transitions. As a result, ALS-related mutants may disrupt various aspects of SG homeostasis by directly disturbing the intermolecular interactions or affecting core SG components, thus disrupting the phase equilibrium of the cytoplasm during stress. Considering that the importance of the "global view" of SG homeostasis in ALS pathogenesis has not received enough attention, we first systematically summarize the physiological regulatory mechanism of SG homeostasis based on LLPS and then examine ALS pathogenesis from the perspective of disrupted SG homeostasis and aberrant phase transition of biomacromolecules.

Short disordered termini and proline-rich domain are major regulators of UBQLN1/2/4 phase separation

“…Here, we present a third possible mechanism through the distinct phase transitions of UBQLN1, UBQLN2, and UBQLN4. Aberrant phase transitions of proteins associated with neurodegeneration lead to aggregation and disease ( 22 , 36 , 37 , 38 ). As all three UBQLNs are involved in neurodegenerative diseases and colocalized with cellular condensates and protein aggregates, their different propensities to undergo phase transitions can contribute to their similar but distinct cellular functions and possibly disease states when dysregulated.…”

TRIM25 predominately associates with anti-viral stress granules

“…In addition to diverse environment insults, genetic mutations, aging, and other chronic stresses could also induce the formation of pathological SGs 9 , 63 – 65 . As a consequence, disturbance in SG dynamics has been regarded as a major driver for many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) 9 , 63 , 64 . Moreover, a recent study reveals that diverse Charcot-Marie-Tooth type 2 neuropathies (CMT2)-causing mutants share the same properties by abnormally entering the SG network 66 .…”

Short N-terminal disordered regions and the proline-rich domain are major regulators of phase transitions for full-length UBQLN1, UBQLN2 and UBQLN4

“…Here, we present a third possible mechanism through the distinct phase transitions of UBQLN1, UBQLN2 and UBQLN4. Aberrant phase transitions of proteins associated with neurodegeneration lead to aggregation and disease (Alberti and Hyman, 2021; Li et al, 2022; Molliex et al, 2015; Patel et al, 2015). As all three UBQLNs are involved in neurodegenerative diseases and colocalized with cellular condensates and protein aggregates, their different propensities to undergo phase transitions can contribute to their similar but distinct cellular functions and possibly disease states when dysregulated.…”