Mechanisms of protein toxicity in neurodegenerative diseases

Abstract

Protein toxicity can be defined as all the pathological changes that ensue from accumulation, mis-localization, and/or multimerization of disease-specific proteins. Most neurodegenerative diseases manifest protein toxicity as one of their key pathogenic mechanisms, the details of which remain unclear. By systematically deconstructing the nature of toxic proteins, we aim to elucidate and illuminate some of the key mechanisms of protein toxicity from which therapeutic insights may be drawn. In this review, we focus specifically on protein toxicity from the point of view of various cellular compartments such as the nucleus and the mitochondria. We also discuss the cell-to-cell propagation of toxic disease proteins that complicates the mechanistic understanding of the disease progression as well as the spatiotemporal point at which to therapeutically intervene. Finally, we discuss selective neuronal vulnerability, which still remains largely enigmatic.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Frontotemporal dementia; Huntington’s disease; Lou Gehrig’s disease; Parkinson’s disease; Polyglutamine diseases; Protein inclusions; Stress granules.

Fig. 1

A schematic overview of protein toxicity. Accumulation of toxic disease proteins is shown to induce dysfunctions in specified compartments such as the nucleus, mitochondria, cytoplasm, and stress granules. They can also propagate into other nearby cells, spreading the disease pathology

Fig. 2

Propagation of misfolded proteins via intercellular transmission. Gradual change in the distribution of α-synuclein (a) and tau (b) inclusions in the brains of patients suffering from Parkinson’s (a) and Alzheimer’s (b) diseases. c Intercellular transmission of misfolded proteins via exocytosis, endocytosis, exosomes, and tunneling nanotubes