The progressive accumulation of ?-synuclein intracellular inclusions in the nervous system is a characteristic feature of dementia with Lewy bodies and Parkinson's disease which are part of a spectrum of sporadic and hereditary neurodegenerative diseases termed ?-synucleinopathies. The definitive involvement of ?-synuclein in the etiology of these disorders was established by the findings that mutations in ?-synuclein can directly cause these neurodegenerative disorders. Many studies suggest that the progressive spread of ?-synuclein pathology in the peripheral nervous system and the brain through direct ?-synuclein interactions and transmission between cells may contribute to disease progression. However, some studies characterizing the properties of novel ?- synuclein mutants demonstrated divergent effects that are not consistent with this simple spreading mechanism. It is also important to emphasize that there is still ongoing debate as to the nature of the toxic ?-synuclein species. To provide new insights on these contentious and critical issues that will address the unique properties of disease-associated ?-synuclein mutants, we have formed a team of experienced investigators with diverse and unique expertise.
In Aim 1, we will determine the inherent aggregation and neurotoxicity properties of these novel ?-synuclein mutants in vivo and compare these outcomes to the more extensively characterized ?-synuclein mutants.
In Aim 2, we will test the hypothesis that in vivo prion-like seeding can differentially impact the induction and propagation of ?-synuclein inclusion pathology of disease-causal ?-synuclein mutants with unique stain-like properties. These studies will provide pivotal information regarding the neurotoxicity of abnormal forms of ?-synuclein, their impact of the induction and spread of ?-synuclein pathology and the associations with neurodegeneration.
Parkinson's disease, dementia with Lewy bodies and the related spectrum of neurodegenerative disorders are characterized by the progressive accumulation of ?-synuclein inclusions in the nervous system. The proposed studies will characterize the pathological and physiological properties of newly characterized mutant ?-synuclein proteins that are genetically associated with these disorders. These findings will provide pivotal information regarding the interplay between abnormal forms of ?-synuclein, ?-synuclein aggregation and neuronal impairments, which will shed light on neurodegenerative mechanisms.
| Sorrentino, Zachary A; Vijayaraghavan, Niran; Gorion, Kimberly-Marie et al. (2018) Physiological C-terminal truncation of ?-synuclein potentiates the prion-like formation of pathological inclusions. J Biol Chem 293:18914-18932 |
