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The Impact of Transglutaminase 2 on the Toxicity of alpha-Synuclein: Implications for Parkinsonís Disease

Hilary Grosso
B.S., New York University Ė 2006

Thesis Advisors: M. Maral Mouradian, M.D.
Graduate Program in Neuroscience

RWJMS Research Tower
Ground Floor, Room V-14

Tuesday, January 31, 2012
10:30 a.m.


Neurodegenerative diseases are a class of progressive disorders that involve the loss of neuronal cells leading to characteristic motor and cognitive impairments. While the manifestations of these diseases vary, the underlying neuropathologic processes share many similarities, including the formation of protein aggregates containing disease-specific proteins in affected cells. These aggregates or intermediates in their formation are believed to be neurotoxic and, therefore, identifying factors involved early in their development could aid in developing neuroprotective therapies for these disorders. TG2 is one such potential factor. Mounting evidence suggests a role for this cross-linking enzyme in these diseases, including the findings that TG2 protein, mRNA, and enzymatic activity are increased in a number of neurodegenerative disorders, and that many disease-associated proteins are susceptible to TG2-mediated cross-linking. In particular, alpha-Synuclein, a key protein in Parkinsonís disease (PD), is a substrate for TG2 leading to its aggregation. In this project, we examined the role of TG2 in alpha-Synuclein toxicity in two model systems. We first show that in a yeast model, TG2 exacerbates the growth impairment caused by alpha-Synuclein expression and accelerates the formation of alpha-Synuclein aggregates. In a mouse model, over-expression of TG2 exacerbates the behavioral and neuropathologic phenotype associated with alpha-Synuclein over-expression, while deletion of the TG2 gene is protective. In mice double transgenic for TG2 and alphpa-Synuclein (TG2Tg/SynTg), this increased toxicity manifests as worse motor performance, increased disruption of nerve fibers and hippocampal neuronal activity, and increased markers of neuroinflammation. All these indices of an aggravated phenotype correlate with greater accumulation of potentially toxic species of alpha-Synuclein, including its insoluble and phosphorylated forms, relative to single transgenic SynTg mice. On alpha-Synuclein and lacking TG2 (TG2-/-/SynTg) are relatively protected against the toxicity of alpha-Synuclein with a trend toward improved motor performance and reduction of phosphorylated alpha-Synuclein compared to SynTg mice. Taken together, these results implicate TG2 as an important element in the pathogenesis of PD, and suggest that it is a viable target for therapeutic interventions aimed at disease modification in PD and other alpha-Synucleinopathies.

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