# Molecular Assessment of Cause and Consequence of Cellular Senescence in Diverse Midbrain Cell Types in Parkinson's Disease

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2024 · $381,733

## Abstract

PROJECT SUMMARY/ABSTRACT
Parkinson's disease is the second most common age-related neurodegenerative disorder. The underlying cause of
idiopathic Parkinson's is unknown. Importantly, prodromal inflammation of the midbrain has been found but remains
unexplained. Recently, we have discovered that dopaminergic neurons can enter a state of cellular senescence and
found significantly elevated numbers of senescent cells in the midbrain of human Parkinson's disease patients.
Cellular senescence is a program that gets activated upon DNA damage signaling and prevents mitotic cells from
uncontrolled proliferation. Most senescent cells express the so-called senescence associated secretory phenotype.
This phenotype is characterized by the secretion of proinflammatory factors that recruit immune cells and signal
“come here and eat me!”. We have also found that senescent human and mouse dopaminergic neurons secrete
pro-inflammatory factors and get removed by activated glial cells. The rationale underlying this proposal is that
cellular senescence is a generic mechanism in the midbrain leading to dopamine neuron loss which results in
Parkinson's disease. The three aims of the proposal focus on 1) unravelling the parkinsonism-related in vitro triggers
of cellular senescence in dopaminergic neurons; 2) the characterization of senescence-mediated activation of
immune responses and the in vitro spreading of senescence between cell types of the midbrain; and 3) the in vivo
induction and spreading of senescence between diverse cell types in the midbrain. In the proposed study, we will
identify pathways that induce cellular senescence in dopaminergic neurons and identify factors which are crucial for
the spreading of senescence and the activation of an immune response. Finally, we will assess whether ablation of
senescent cells in the midbrain at the right time point will interfere with the spreading and can thereby ameliorate the
loss of dopaminergic neurons of the midbrain. The molecular understanding of the induction of senescence as well
as the identification of released factors that are important to trigger brain inflammation will shed light on the general
pathomechanism of Parkinson’s disease and other age-related neurodegenerative disorders. Moreover, our findings
will have direct clinical implications to eventually develop methods to interfere with midbrain senescence to
ameliorate the progression of Parkinson’s disease.

## Key facts

- **NIH application ID:** 10872261
- **Project number:** 5R01NS124735-03
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Markus Riessland
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $381,733
- **Award type:** 5
- **Project period:** 2022-07-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872261

## Citation

> US National Institutes of Health, RePORTER application 10872261, Molecular Assessment of Cause and Consequence of Cellular Senescence in Diverse Midbrain Cell Types in Parkinson's Disease (5R01NS124735-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10872261. Licensed CC0.

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