The Norepinephrine transporter as a therapeutic target for treatment of alpha-synuclein pathology in PD

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The Norepinephrine transporter as a therapeutic target for treatment of alpha-synuclein pathology in PD Parkinson’s disease (PD) is a neurodegenerative disorder prevalent in ~1% of the population, making it a medically important problem, especially in the aging population. The economic burden for PD exceeds $10 Billion annually in the US and the prevalence of PD is projected to significantly increase in the coming decades. PD is characterized by severe motor deficits as well as non- motor symptoms such as loss of smell, constipation and cognitive disability. Sporadic PD is characterized by widespread alpha-synuclein (α-syn) positive inclusions called Lewy bodies and neurites in the brain, along with loss of dopamine neurons of the substantia nigra pars compacta (SNpc). However, the underlying mechanisms of α-syn mediated pathogenesis, progression, and neurodegeneration are still not clear. Consequentially, strategies for treating pathogenesis and progression of sporadic PD have not been well developed. Previous studies and our preliminary data suggest that the norepinephrine transporter (NET) is a potential therapeutic target for α-syn pathology in PD. Our overall hypothesis is that genetic deletion or pharmacological inhibition of NET will reduce α-Syn propagation, neurodegeneration, neuroinflammation and behavioral deficits. We will test our hypothesis through two aims. In aim1, we will test the effect of NET deletion or inhibition on histological markers of α-syn aggregation and propagation, dopamine neurodegeneration and neuroinflammation. In aim2, we will test the effect of NET deletion or inhibition on motor deficits. The proposed experiments will not only provide an insight into the underlying mechanism of α- syn propagation and vulnerability, but more importantly reveal a potential therapeutic strategy for ameliorating functional impairments and slow progression of PD pathology.