Project Details
Description
Despite intensive research, the etiology leading to neuronal cell loss in Parkinson’s disease (PD) remains
unknown. There is compelling evidence that changes in histone acetylation are implicated in cognition and brain
function and that aberrant histone acetylation is associated with neurodegenerative diseases and aging. However,
there is currently no mechanistic insight about the cause and how dysregulated histone acetylation is functionally
linked to age-related neurodegenerative disorders such as PD.
To functionally dissect the role of histone acetylation in the pathogenesis of PD, we have developed a human
pluripotent stem cell (hPSC)-based discovery platform that allows to dissect a-Syn toxicity in neuronal cells. We
show that this system provides a robust, scalable system with disease-relevant phenotypes in neuronal cells.
Importantly, this approach can be applied to CRISPR/Cas9 screens to identify modifiers of a-Syn toxicity.
Using this discovery platform, we intersected SILAC proteomics and genome-wide CRISPR-screening data
and identified modifiers of histone acetylation to contribute to a-Syn toxicity. Consistent with these in vitro results,
our pilot studies confirm similar changes in histone acetylation in PD postmortem brain tissue. Considering that
a key function of histone acetylation is to modulate gene expression, we speculate the dysregulated transcription,
resulting from a-Syn-mediated disruption of histone acetylation modifying enzymes, contributes to the
neurodegeneration in PD.
The main goal of this proposal is to determine the functional role of histone acetylation in PD at the molecular
and cellular level. Specifically, we will apply our novel functional genomics platform to determine the effect of
modulating histone acetylation by gain and loss of function of acetylation modifying enzymes in a-Syn-mediated
impairment of neuronal function and neuronal cell death. In addition, we will use molecular and epigenomics
approaches to identify the chromatin regulated gene expression signature associated with a-Syn toxicity.
Considering that a-Syn pathology is central to most familial and sporadic forms of PD, we will expand our
molecular and epigenetic analysis to include a wide range of patient-derived hiPSC-based models and
postmortem brain tissue to confirm that aberrant histone acetylation pays a central role in the pathogenesis of
PD.
Successful completion of the proposed experiments will provide fundamental mechanistic insights into the
epigenetics of PD. Given that drugs targeting histone modifiers are currently being developed as therapeutics,
there is considerable interest in understanding how modulating histone acetylation could be used to treat
neurodegenerative disease, cognitive decline, and ageing. Importantly, the comparison of our findings with
available data for aging and Alzheimer’s disease will allow the interpretation of PD-associated epigenetic
changes in a broader context of neurodegenerative diseases and aging and provide a molecular starting point
to functionally understand how genetic and non-genetic factors interact in the etiology of complex
neurodegenerative diseases.
Status | Active |
---|---|
Effective start/end date | 7/11/23 → 6/30/24 |
Funding
- National Institute of Neurological Disorders and Stroke: $624,231.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.