Age is the largest risk factor for Parkinson’s disease (PD) with incidence rising exponentially above the age of sixty. Why this is true has been the subject of speculation, but little rigorous study. There is a growing body of experimental work arguing that accumulated cellular damage with aging triggers the induction of senescence in both neurons and glia. The accumulation of senescence cells can cause dysfunction, neurodegeneration and inflammation. DNA and mitochondrial damage – both known triggers of senescence in peripheral tissues – are evident in the region of the brain most affected by PD, the substantia nigra pars compacta (SNc). In addition, there also is an accumulation of senescent neurons. The proposed project builds upon these observations to test the hypothesis that SNc dopaminergic neurons, the neurons responsible for the core motor symptoms of PD are predisposed to the induction of senescence following DNA or mitochondrial damage and that senescence leads to changes in cellular properties underlying PD symptoms. Moreover, we hypothesize that senescence amplifies the pathological consequences of genetic mutations associated with familial forms of the disease. Lastly, we hypothesize that the senescent phenotype can be reversed, leading to restoration of function and alleviation of symptoms. Two parallel lines of study are proposed to test this overarching model. First, using intersectional genomics, we will perturb mitochondrial function and DNA structure in ways that will rapidly induce senescence in defined cell lineages. These perturbations can be performed in young mice, eliminating confounding effects of aging outside the brain, mitigating the experimental difficulties of working with aged animals and speeding the experimental cycle time. Both perturbations are reversible, allowing us to assess the feasibility of rescuing senescent neurons and the effect this will have on behavior. Second, CRISPR-cas9 methods will be used to introduce the same perturbations in human neurons, allowing a direct comparison between human and rodent cells at key stages during induction and reversion of senescence. A team of highly accomplished investigators – Drs. Surmeier, Krainc and Schumacker – with complementary expertise in cutting-edge methodologies has been assembled to complete this project.
|Effective start/end date||1/1/18 → 10/31/20|
- Michael J. Fox Foundation for Parkinson's Research (15031)
Clustered Regularly Interspaced Short Palindromic Repeats