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Funded Studies

Autophagy in Dopamine Neurons: Clearance of Alpha-synuclein and Neuroprotection

The central hypothesis for the cellular mechanism of Parkinson’s disease is the toxic accumulation of alpha-synuclein, dysfunctional protein clearance and oxidative stress collectively leading to the degeneration of dopaminergic neurons. Autophagy is a regulated lysosomal degradation which has the capacity to clear large protein/lipid complexes, toxic aggregates and cellular organelles. Current pre-clinical models with overexpression of human mutant alpha-synuclein do not display Lewy body-like inclusions in dopamine neurons. The absence of inclusions could be due to highly active autophagy that prevents the accumulation of exogenous alpha-synuclein. Furthermore, autophagy-lysosomal function declines with age in human brain, which in part due to the high oxidative stress. Therefore, we hypothesize that neuronal autophagy is critical for the regulation of alpha-synucleinprotein levels and protective against neuronal death; dysfunction of autophagy predisposes to the pathogenesis of PD in dopamine neurons.

To test this, we will establish conditional knock-out mice in which an essential autophagy gene, Atg7, is deleted specifically in dopamine neurons. We will use these pre-clinical models to investigate whether alpha-synuclein wildtype or PD-mutant A53T will be accumulated and deposited into Lewy body-like inclusions in the mutant dopamine neurons. In addition, we will study the effect of inactivation of autophagy on oxidative stress level, striatal dopamine content and dopamine neuron degeneration. This study will provide valuable information for the evaluation of autophagy as a drug target for the treatment of PD.

Final Outcome

Dr. Yue’s results suggest that neuronal autophagy is critical for the regulation of alpha-synuclein protein levels and protective against neuronal death; dysfunction of autophagy may predispose dopamine neuron to PD-like pathology.

The researchers found that loss of autophagy caused accumulation of alpha-synuclein protein in the brain. Specific disruption of autophagy in midbrain dopamine neurons led to early dystrophic axons and reduced dopamine levels in the dorsal striatum. In addition, the mutant dopamine neurons develop ubiquitinated, p62-positive inclusions throughout the cell bodies and dendrites of the substantia nigra in models.

Interestingly, autophagy suppression resulted in a late and moderate loss of midbrain dopamine neurons in the substantia nigra, accompanied by impairment of locomotor activity. Therefore, this study presents a unique model with progressive and slow degeneration of dopamine neurons in midbrain.


  • Zhenyu Yue, PhD

    New York, NY United States

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