Abstract:

Alzheimer’s and Parkinson’s diseases are neurodegenerative disorders pathologically classified by the accumulation of amyloidogenic proteins into insoluble inclusions within the brain. Specifically, amyloid plaques in the brains of Alzheimer’s disease patients are comprised of amyloid-β (Aβ) peptide, the product of sequential cleavage of the amyloid precursor protein by β- and γ-secretases. Simil arly, α-synuclein is a major component of Lewy bodies associated with Parkinson’s disease. Though both diseases increase progressively with disease and age, the soluble oligomeric forms associated with each polypeptide are, arguably, the most toxic species. Both Aβ and α-synuclein form porous oligomers that permeabilize membranes. Intracellular α-synuclein obstructs endoplasmic reticulum-Golgi traffic and following internalization, Aβ rapidly aggregates in endosomes and lysosomes. Using transgenic Caenorhabditis elegans models of neurodegeneration, Griffin et al. (2018) show that the homotypic fusion protein sorting complex, HOPS, lies at an intersection between the two pathogenic proteins to functionally protect against neurodegeneration.