Pathological phase transitions in ALS-FTD impair dynamic RNA–protein granules

Abstract

The genetics of human disease serves as a robust and unbiased source of insight into human biology, both revealing fundamental cellular processes and exposing the vulnerabilities associated with their dysfunction. Over the last decade, the genetics of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have epitomized this concept, as studies of ALS-FTD-causing mutations have yielded fundamental discoveries regarding the role of biomolecular condensation in organizing cellular contents while implicating disturbances in condensate dynamics as central drivers of neurodegeneration. Here we review this genetic evidence, highlight its intersection with patient pathology, and discuss how studies in model systems have revealed a role for aberrant condensation in neuronal dysfunction and death. We detail how multiple, distinct types of disease-causing mutations promote pathological phase transitions that disturb the dynamics and function of ribonucleoprotein (RNP) granules. Dysfunction of RNP granules causes pleiotropic defects in RNA metabolism and can drive evolution of these structures to end-stage pathological inclusions characteristic of ALS-FTD. We propose that aberrant phase transitions of these complex condensates in cells provide a parsimonious explanation for the widespread cellular abnormalities observed in ALS as well as certain histopathological features that characterize late-stage disease.

Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy

“…Moreover, C9ORF72 knockout mice exhibited strikingly different survival rates depending on their environment and microbiome [ 65 ]. G4C2 repeats were transcribed as RNA and accumulated in the nucleus of nerve cells to form RNA foci by a liquid–liquid phase separation (LLPS) mechanism [ 66 ]. Furthermore, G4C2 repeat RNA and its translation product, dipeptide repeat protein, have been reported to cause neurodegeneration by increasing DNA double-strand breaks, leading to a deficiency of ataxia telangiectasia mutated (ATM), which repairs DNA damage [ 67 ].…”

Principles and functions of condensate modifying drugs

“…SGs are also composed of many disease-associated intrinsically disordered RNA-binding proteins such as TDP43 and FUS ( Nedelsky and Taylor, 2022 ), and their persistence is implicated in the pathophysiology of ALS ( Fang et al, 2019 ; Dudman and Qi, 2020 ). Unresolved persistent stress granules evolve into disease-associated pathological aggregates, such as those seen in spinal cord motor neurons of ALS patients, resulting in a gain and/or loss-of-function of the sequestered molecular community ( Alberti and Hyman, 2021 ; Nedelsky and Taylor, 2022 ). Two scenarios for targeting these SG condensatopathies might have clinical relevance: 1) specifically dissolving the persistent SGs; 2) inhibiting the formation of SGs.…”

Quantifying Coexistence Concentrations in Multi-Component Phase-Separating Systems Using Analytical HPLC

“…Indeed, evidence is accumulating that cancer pathogenesis can be mediated by either the abrogation of functional condensates through mutations of scaffolding molecules [ 21 ], or by the creation of aberrant condensates through the fusion of phase separating molecules with effector domains via chromosomal translocations [ 22 , 23 , 24 ]. Aberrant maturation of condensates is also thought to underlie the pathogenesis of a spectrum of neurodegenerative diseases [ 25 , 26 , 27 , 28 , 29 , 30 ].…”