The mechanisms of protein toxicity in neurodegenerative diseases

Abstract

With increasing life expectancy, neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Huntington’s disease (HD), have become one of the major threats to humans. Although the symptoms vary depending on the type of disease, these neurodegenerative diseases share protein toxicity as one of their key pathogenic mechanisms. Herein protein toxicity is defined as all the pathological changes that ensue from accumulation, mis-localization and/or oligomerization of disease-associated toxic proteins such as α-synuclein in PD, polyglutamine (polyQ)-containing proteins in polyQ diseases (e.g., HD), and SOD1 and TDP-43 in ALS. Protein toxicity in affected neurons encompasses a number of cellular defects, such as mitochondrial dysfunction, impaired protein/RNA quality control, and neuronal cell death, all of which critically contribute to the initiation and progression of the diseases. Thus, strengthening our understanding of the nature of protein toxicity is essential for the development of effective therapeutics for these diseases. In this talk, I will present our current understanding on the molecular and cellular mechanisms of protein toxicity in neurodegenerative diseases, particularly in the context of polyglutamine (polyQ) diseases, based on our ongoing studies.