Towards Understanding the Initiating Role of Truncated Alpha-Synuclein in Neurodegeneration

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Project Summary/Abstract: Dementia afflicts 47 million individuals worldwide and has an economic impact of more than $800 billion; neurodegenerative diseases for which no disease modifying therapies exist are the most common etiology. α-synuclein (αS) aggregates into toxic fibrils in multiple neurodegenerative diseases where the fibrils form characteristic inclusions implicated in disease progression. Mechanisms through which initial αS fibrils form is unclear, and yet halting their appearance is key to preventing disease. Carboxy-terminal truncation (C-truncation) of αS may be crucial in disease pathogenesis, as it has been repeatedly shown in- vitro that C-truncated αS spontaneously assembles into fibrils more readily than full-length αS. Proteolytic formation of these truncated species, possibly promoted by aging associated lysosomal impairment, may be key to initial pathology formation in disease. Additionally, C-truncated αS is increased in disease suggesting a pathologic role, where 15-20% of αS in inclusions is truncated. Therefore, The Aims of this project are to characterize naturally formed C-truncated species of αS for their ability to aggregate into pathologic fibrils and stimulate synergistic formation of αS and tau pathology in-vivo. Specific Aim one: Investigate the propensity of physiologic C-terminally truncated αS to pathologically aggregate in-vitro and in cellular models of synucleinopathy and tauopathy. Herein, I will characterize the aggregation propensity of naturally formed C-truncated αS both in-vitro and in-vivo using well characterized models. My working hypothesis is that truncated forms of αS will aggregate readily and synergistically induce full-length αS and tau fibril formation. These results will elucidate molecular mechanisms of aggregation and set the stage for further in-vivo work. Specific Aim two: Determine the ability of physiologic C-terminally truncated αS to initiate pathology in mouse models of synucleinopathy and tauopathy utilizing cerebral fibril injection and recombinant adeno associated virus (rAAV). Viral overexpression of familial aggregation prone αS mutants in mice results in neurodegenerative features used to model disease. Additionally, injection of preformed αS fibrils has been found to hasten progression of the disease in transgenic animals. My working hypothesis is that injection of truncated αS fibrils, and conversely rAAV overexpression of truncated αS in mice will initiate αS and tau pathology. These experiments will uncover pathogenic roles for αS truncation in neurodegenerative diseases.