Grant: Project Grant

Parkinson's disease is a degenerative condition of the brain that is characterized by tremor, stiffness and slowness. These motor manifestations are caused by a reduction of a chemical substance called dopamine in the striatum, a brain area that is key to the production of movement. There is no treatment to slow the progression of the illness. Although the reasons for this reduction of dopamine remain unclear, there is increasing evidence indicating that an abnormal accumulation of the protein "alpha-synuclein" in the brain plays an important role. The effects of alpha-synuclein accumulation on the cellular populations of the brain remain incompletely understood, notably early in the process, before Parkinson's disease becomes apparent, or when its manifestations are still mild. What if a better understanding of the changes triggered by alpha-synuclein on brain cells during early Parkinson's disease held the key to discovering treatments that would slow its progression? Here, we propose to seek answers to this important question. We have developed an experimental model of Parkinson's disease through intracerebral delivery of alpha-synuclein. Our model recapitulates the evolution of the human condition, with progressive emergence of motor features, brain accumulation of alpha-synuclein, and reduced dopamine in the striatum. We propose to further characterize our model and utilize it to examine the effects of alpha-synuclein accumulation on the brain cells before and after the appearance of motor manifestations. To do so, we will perform state-of-the-art stainings of different cell populations, as well as cutting-edge techniques called single-nucleus RNA sequencing and spatial transcriptomics, which will enable us to determine specific properties of different cell populations in brain areas that are involved in the disease. Lastly, we will seek to interfere with alpha-synuclein accumulation, which could have important clinical implications.