Autophagy and Proteostasis: A Unifying Theory of ­Neurodegenerative Disease

Abstract

Progressive neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease are a major public health burden. Neurodegenerative diseases have a common pathophysiology of protein aggregate formation but the exact mechanism of neuronal destruction has not been pinpointed. Various theories have been proposed in the literature to explain the underlying causes of these diseases, including reactive oxygen species generation, mitochondrial dysfunction, excessive neuroinflammation, microglial cell dysfunction, and others. These neurodegenerative diseases appear to be multifactorial and complex in origin, and there are no treatments or approved drugs that can halt the disease progression. Recent genetic and basic science research into the mechanisms of neurodegenerative diseases have implicated a new paradigm that incorporates the previous theories into a more cohesive conceptual framework. A failure to balance neuronal autophagy and lysosomal function may be the common root cause of these disorders that can lead to mitochondrial dysfunction, excessive protein aggregation, increased reactive oxygen species generation and inflammation. This review examines the current research on autophagy and new drug and/or natural product approaches to enhancing partial autophagy that can help prevent neuronal death and the progression of neurodegenerative disease. The critical factor in brain health may be the balance of autophagy and cell death in maintaining viable neurons.