Alpha-Synuclein Aggregates as an Inducer of Glial Senescence: Potential Role in Parkinson's Disease

Study Rationale:                             
Cellular senescence (deterioration) is a critical factor of biological aging that occurs in almost all peripheral tissues but little is known about its role in age-related neurodegenerative disorders, such as Parkinson's disease (PD). Senescence occurs in dividing cell types and halts cell proliferation (growth) in an irreversible manner. This process is caused by stress and puts cells at risk for tumor formation. Once established, these cells express a senescence-associated secretory phenotype (SASP), the pro-inflammatory secretion of cytokines and other factors that contribute to the age-related loss of peripheral tissue function. We aim to interrogate induction of senescence and SASP in response to alpha-synuclein (protein clumps) within the most prevalent dividing cell type in the brain, the astrocyte (cells that provide support and clean waste in the brain), and how this in turn affects dopaminergic cell health in relation to PD.

Hypothesis:
We will explore whether induction of astrocytic senescence occurs in response to
alpha-synuclein aggregation and, if so, whether it also contributes to PD progression. We will also investigate whether senescence cell ablation (removal) prevents neuropathological phenotypes associated with the disorder.

Study Design:
In the first part of this project, we will explore whether alpha-synuclein aggregation, widely considered to be a key pathological feature associated with PD, results from the induction of cellular senescence and SASP within human induced pluripotent stem cell (iPSC)-derived astrocytes in culture and whether this can drive pathology in neighboring neurons. In the second part of this project, we will test induction of astrocytic senescence in pre-clinical models that display alpha-synuclein aggregation within these cells and, importantly, whether senescent cell ablation prevents neuropathological and locomotor defects associated with these models.

Impact on Diagnosis/Treatment of Parkinson’s disease:                              
Findings from these studies will provide important information regarding a new biological pathway that may contribute to PD neuropathology and could identify an unexplored therapeutic target for the disease. 

Next Steps for Development:
If our hypothesis proves correct, these results will open the door for pre-clinical and clinical testing of pharmaceutical senolytics (drugs that can kill senescent cells) as novel treatments for PD.