Molecular mechanisms of alpha-synuclein induction and spread of pathobiology

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The presynaptic protein α-synuclein (αS) can aberrantly polymerize to form brain pathological inclusions in a spectrum of neurodegenerative diseases, such as Parkinson’s disease and Lewy body dementia, which are collectively termed “α-synucleinopathies”. Genetic and neuropathological findings provide compelling evidence for the toxic role of aggregated αS in disease progression. Studies from our group and many others have demonstrated that αS has the ability to aggregate intracellularly and to spread between cells by conformational templating prion-like mechanisms. However, it is still unclear what physiological alterations trigger the initial formation of αS inclusion pathology and what αS variants might be responsible for characteristic strain-like transmission that might explain the diversity of synucleinopathies. We demonstrated that many of the physiological carboxy-truncated αS species display significantly greater propensity to spontaneously self-aggregate and promote the aggregation of intact αS. Furthermore, some of these carboxy truncated forms of αS are more potent at mediating prion-like conformational templating of αS inclusions when combined with full length αS but each carboxy-truncated forms of αS also display unique biochemical and propagation kinetic properties. Paradoxically the excess of some forms of carboxy-truncated αS can actually reduce the ability of αS to propagate pathology. Using a novel series of monoclonal antibodies specific for carboxy-truncated forms of αS, we recently published that the neuroanatomical distribution and relative presence of carboxy-truncated forms of αS within pathological inclusions differs between different types of synucleinopathies. We hypothesized that these differences may be driven by the biological effects associated with distinct carboxy-truncated forms of αS. Some of these modified forms of αS many yield polymers with varied propagation kinetic properties while others may inhibit effective neuroanatomical propagation of αS pathology. To address these important questions on the biological mechanisms involved in the initiation and modulation of αS pathological progression, we propose the following complementary Specific Aims. 1) We will determine the propensity of the major physiological carboxy-truncated forms of human αS to initiate and potentiate the propagation of αS pathology using a novel humanized mouse model expressing wild type αS. 2) We will determine the extent of which the presence of the major physiological carboxy-truncated forms of human αS can regulate the spread of αS pathology following seeded initiation. 3) We will determine the extent of which carboxy truncated forms of αS dictates the activities to propel the spread of αS pathology with unique strain-like properties associated with distinctive histological and biochemical features, neuroanatomical distribution and neurodegeneration outcomes in our humanize mouse model expressing wild type αS. Collectively, these studies will provide insights on the function of physiological carboxy-truncated forms of αS in modulating the spread and type of αS pathology that can be responsible for the varied spectrum of synucleinopathies.