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

• Published in: RNA (Cambridge) 2022-01, Vol.28 (1), p.97-113
• Main Authors: Nedelsky, Natalia B, Taylor, J Paul
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Binding Sites; Biomolecular Condensates - chemistry; Biomolecular Condensates - metabolism; Cell Death - genetics; Cytoplasmic Ribonucleoprotein Granules - chemistry; Cytoplasmic Ribonucleoprotein Granules - genetics; Cytoplasmic Ribonucleoprotein Granules - metabolism; Dementia disorders; Frontotemporal dementia; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Frontotemporal Dementia - pathology; Humans; Molecular Dynamics Simulation; Mutation; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurodegeneration; Neurons - metabolism; Neurons - pathology; Phase Transition; Phase transitions; Protein Binding; Ribonucleoproteins - chemistry; Ribonucleoproteins - genetics; Ribonucleoproteins - metabolism; RNA - chemistry; RNA - genetics; RNA - metabolism; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism
• ISSN: 1355-8382; 1469-9001
• DOI: 10.1261/rna.079001.121

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 the 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.