Study Rationale:
Age is the biggest risk factor for Parkinson's disease (PD), with disease incidence rising steeply among persons 60 or older. The reason for this remains unknown. Research suggests that damage accumulated in cells with age leads to senescence (breakdown) in nerve and glial cells in the brain. Senescence, in turn, can cause neurodegeneration and inflammation. Damage to DNA and mitochondria (cell's energy generators) - both known triggers of senescence outside the brain - are evident in the region of the brain most affected by PD, the substantia nigra pars compacta (SNc).
Hypothesis:
In the proposed study, we will test the hypothesis that dopamine-producing cells in SNc -- the cells responsible for the motor symptoms of PD -- become senescent easily following DNA or mitochondria damage. We also aim to test whether senescence changes cellular properties underlying Parkinson's symptoms. Moreover, we hypothesize that senescence magnifies the effects of genetic changes (mutations) associated with inherited forms of Parkinson's disease. Lastly, we hypothesize that the state of senescence can be reversed, leading to restoration of function and alleviation of symptoms of PD.
Study Design:
To test these hypotheses, we propose two lines of study. First, we will rapidly induce senescence in different types of cells by changing mitochondrial function and DNA structure. These changes can be performed in young pre-clinical models. The advantages of working with young pre-clinical models include the lack of unwanted effects of aging outside the brain, the ease of working with young pre-clinical models and a faster pace of work. Both DNA and mitochondria changes are reversible, which would allow us to assess the feasibility of reversing senescence in nerve cells and the effect of this on behavior. Second, cutting-edge techniques will be used to make the same changes in human nerve cells, allowing a direct comparison between human cells and cells from pre-clinical models during induction and reversion of senescence.