Proteostasis and Ribostasis Impairment as Common Cell Death Mechanisms in Neurodegenerative Diseases

The cellular homeostasis of proteins (proteostasis) and RNA metabolism (ribostasis) are es-sential for maintaining both the structure and function of the brain. However, aging, cellular stress conditions, and genetic contributions cause disturbances in proteostasis and ribostasis that lead to protein misfolding, insoluble aggregate deposition, and abnormal ribonucleopro-tein granule dynamics. In addition to neurons being primarily postmitotic, nondividing cells, they are more susceptible to the persistent accumulation of abnormal aggregates. Indeed, de-fects associated with the failure to maintain proteostasis and ribostasis are common patho-genic components of age-related neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, the neuronal deposition of misfolded and aggregated proteins can cause both increased toxicity and impaired physio-logical function, which lead to neuronal dysfunction and cell death. There is recent evidence that irreversible liquid-liquid phase separation (LLPS) is responsible for the pathogenic ag-gregate formation of disease-related proteins, including tau, alpha-synuclein, and RNA-binding proteins, including transactive response DNA-binding protein 43, fused in sarcoma, and het-erogeneous nuclear ribonucleoprotein A1. Investigations of LLPS and its control therefore sug-gest that chaperone/disaggregase, which reverse protein aggregation, are valuable therapeutic targets for effective treatments for neurological diseases. Here we review and discuss recent studies to highlight the importance of understanding the common cell death mechanisms of and ribostasis in diseases.