# Calpain cleavage of α-synuclein and T-cell reactivity in Parkinson’s disease

> **NIH NIH R21** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $411,125

## Abstract

Summary
Parkinson's disease (PD) is a debilitating progressive degenerative movement disorder associated with loss of
dopaminergic (DA) neurons in the substantia nigra (SN) along with the accumulation of α-synuclein (α-syn) in
the brain, activation of microglia, production of inflammatory cytokines/chemokines, infiltration of CD4+ T-cells,
and neurodegeneration. The most potent therapy, L-dopa, does not block disease progression, and the
mechanism of the progressive nature is unclear. Calpain, a cysteine protease regulated by calcium, plays a
pivotal role in SN and SC (spinal cord) degeneration in PD, and its role in α-syn aggregation, activation of
microglia, T cells and their migration indicate calpain to be crucial in promoting the inflammatory process and
disease progression. While calpain-1 cleavage of α-syn promotes synuclein aggregation in PD-like diseases,
the precise involvement of the two major calpain isoforms, calpain-1 and calpain-2, in α-syn presentation to
CD4+ T-cells remains unknown. Preliminary studies here identified a subtype of CD4+ T cells in MPTP mice,
which was abolished by calpain inhibitor, suggesting that activation of calpain and CD4+ T cells may play
critical roles in the inflammatory process and disease progression in PD. Preliminary data also suggest that
siRNA-mediated knockdown of calpain-2 diminishes antigen presentation by human B-cells and inhibits
activation of CD4+ T cells. Thus, we hypothesize that activation of distinct calpain isoforms may favor
expansion of a subtype of α-syn-reactive CD4+ T cells in PD-like disease. We also hypothesize that calpain
inhibition may attenuate α-syn aggregation and expansion of inflammatory T cells, reduce inflammation and
support neuronal survival and improved outcome in PD patients. Two specific aims are proposed to test the
hypothesis: (Aim 1) To investigate whether activation of calpain-1 or calpain-2 is linked with microglial
presentation of α-syn to CD4+ T cells resulting in disease progression and neurodegeneration in PD-like
disease in mice. (Aim 2) To determine whether inhibition of calpain-2 reduces microglial presentation of α-syn
and generation of pathogenic CD4+ T cells, attenuating disease progression in mouse models of PD. The goal
of this study is to investigate the role of calpain-1 and calpain-2 in generating α-syn-reactive pathogenic CD4+
T cells, and whether a subpopulation of CD4+ T cells from MPTP mice can induce PD-like disease in
immunodeficient mice. Studies are planned to determine whether deletion of calpain-1 attenuates α-syn
aggregation and expansion of CD4+ T cells using calpain-1 knockout (KO) mice. In addition, the role of
calpain-2 inhibitor will be assessed in the study of alteration of inflammatory CD4+ T cell response and
production of cytokines/chemokines in calpain-1 KO mice. Testing the effects of distinct calpain isoforms in the
generation of α-syn-reactive pathogenic T cells and induction neuronal death and degeneration may lead to
de...

## Key facts

- **NIH application ID:** 10042307
- **Project number:** 1R21NS118393-01
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** NAREN L BANIK
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $411,125
- **Award type:** 1
- **Project period:** 2020-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10042307

## Citation

> US National Institutes of Health, RePORTER application 10042307, Calpain cleavage of α-synuclein and T-cell reactivity in Parkinson’s disease (1R21NS118393-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10042307. Licensed CC0.

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