Parkinson's disease (PD) is the second most common neurodegenerative disorder and the fastest growing neurologic disease in the world, yet no disease-modifying therapy is available for this disabling condition. Multiple lines of evidence implicate the protein a-synuclein (a-Syn) in the pathogenesis of PD, and as such, there is intense interest in targeting a-Syn for potential disease modification.

α-Synuclein (α-Syn) is a key pathogenic protein in α-synucleinopathies including Parkinson disease (PD) and Dementia with Lewy Bodies. The aggregation of α-Syn is believed to be deleterious and a critical step leading to neuronal dysfunction and death. One of the factors that may contribute to the initial steps of this aggregation is crosslinking through transglutaminase 2 (TG2). We previously demonstrated that overexpression of TG2 exacerbates α-Syn toxicity in mice and yeast by increasing the higher-order species of α-Syn. Herein, we investigated whether deletion of the TG2 encoding gene could mitigate the toxicity of α-Syn in vivo . Compared with α-Syn transgenic (Syn Tg ) mice, TG2 null /α-Syn transgenic mice (TG2 KO /Syn Tg ) exhibited a reduced amount of phosphorylated α-Syn aggregates and fewer proteinase K-resistant α-Syn aggregates in sections of brain tissue. Neuritic processes that are depleted in Syn Tg mice compared to wild-type mice were preserved in double TG2 KO /Syn Tg mice. Additionally, the neuroinflammatory reaction to α-Syn was attenuated in TG2 KO /Syn Tg animals. These neuropathological markers of diminished α-Syn toxicity in the absence of TG2 were associated with better motor performance on the rotarod and balance beam. These results suggest that deleting TG2 reduces the toxicity of α-Syn in vivo and improves the behavioral performance of Syn Tg mice. Accordingly, these findings collectively support pharmacological inhibition of TG2 as a potential disease modifying therapeutic strategy for α-synucleinopathies.

Although Huntington’s disease (HD) is classically considered from the perspective of the motor syndrome, the cognitive changes in HD are prominent and often an early manifestation of disease. As such, investigating the underlying pathophysiology of cognitive changes may give insight into important and early neurodegenerative events. In this review, we first discuss evidence from both HD patients and animal models that cognitive changes correlate with early pathological changes at the synapse, an observation that is similarly made in other neurodegenerative conditions that primarily affect cognition. We then describe how autophagy plays a critical role supporting synaptic maintenance in the healthy brain, and how autophagy dysfunction in HD may thereby lead to impaired synaptic maintenance and thus early manifestations of disease.

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