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. ?-synuclein (?S) aggregates into toxic fibrils in multiple neurodegenerative diseases where the fibrils form characteristic inclusions implicated in disease progression. Mechanisms through which initial ?S fibrils form is unclear, and yet halting their appearance is key to preventing disease. Carboxy-terminal truncation (C-truncation) of ?S may be crucial in disease pathogenesis, as it has been repeatedly shown in- vitro that C-truncated ?S spontaneously assembles into fibrils more readily than full-length ?S. 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 ?S is increased in disease suggesting a pathologic role, where 15-20% of ?S in inclusions is truncated. Therefore, The Aims of this project are to characterize naturally formed C-truncated species of ?S for their ability to aggregate into pathologic fibrils and stimulate synergistic formation of ?S and tau pathology in-vivo.
Specific Aim one : Investigate the propensity of physiologic C-terminally truncated ?S 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 ?S both in-vitro and in-vivo using well characterized models. My working hypothesis is that truncated forms of ?S will aggregate readily and synergistically induce full-length ?S 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 ?S 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 ?S mutants in mice results in neurodegenerative features used to model disease. Additionally, injection of preformed ?S fibrils has been found to hasten progression of the disease in transgenic animals. My working hypothesis is that injection of truncated ?S fibrils, and conversely rAAV overexpression of truncated ?S in mice will initiate ?S and tau pathology. These experiments will uncover pathogenic roles for ?S truncation in neurodegenerative diseases.
Neurodegeneration is the most common cause of dementia, which affects more than 40 million people according to the World Alzheimer Report. Neuronal inclusions containing pathologic alpha-synuclein fibrils are found in several neurodegenerative diseases, and the formation of these toxic fibrils is accelerated by carboxy- terminal truncation of alpha-synuclein. These studies will assess the potential involvement of common truncated forms of alpha-synuclein in disease and probe for potential therapeutic targets relating to their formation.
