# Investigating physiologic and pathophysiologic connections between the Parkinson's disease protein alpha-synuclein and RNA binding proteins

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $831,256

## Abstract

Neuronal aggregation of the protein alpha-synuclein (αS) in Lewy bodies is a hallmark of key
Alzheimer Disease and Related Disorders (ADRDs) including Lewy Body Dementia (LBD),
Parkinson’s disease with dementia (PDD) and mixed AD/LB dementia. Collectively these
disorders affect millions of US citizens. Understanding mechanisms of αS toxicity thus holds key
import for understanding and treating ADRD. αS reversibly associates with cellular membranes
in neurons and this interaction is clearly important for toxicity, but the underlying mechanisms
remain unclear. Moreover, αS is also highly abundant in the cytosol. What αS is doing in different
cellular compartments and how this may be relevant to neurotoxicity when αS abnormally
accumulates in ADRD remains unknown. Our previous extensive genetic and physical αS
interaction mapping connected αS not only to membrane trafficking proteins but also to a
surprising number of RNA-binding proteins (RBPs). However, while RBP dysregulation and loss
of RNA homeostasis are clearly important contributors to neurodegeneration in general, a direct
link between αS and RBPs was elusive until now. We recently found that αS can perturb RNA
homeostasis by directly interacting with and disrupting the mRNA decapping machinery found in
Processing Bodies, membraneless ribonucleoprotein complexes responsible for mRNA turnover.
αS strongly interacts with decapping proteins of P-bodies in neurons. Importantly, the exact same
(N-terminus) αS region is responsible for binding to membranes and to P-body proteins. This sets
up a dichotomous relationship whereby alterations at the membrane can directly affect gene
regulation through redistributing αS between membrane and cytosolic compartments. On the
basis of our findings in human iPSC neurons and postmortem brain, we hypothesize that αS
shuttles between membranes and P-bodies and, upon accumulation to toxic levels, disrupts P-
body composition and mRNA turnover. Model organism and human genetics analyses also
support a causal influence of the P-body pathway in modulating αS toxicity an PD risk. Here, we
will, first, rigorously test these connections by measuring P-body perturbations in a wide-range of
synucleinopathy models, postmortem brain and mouse models and assess the direct impact of
P-body genes on neurotoxicity. Second, we will investigate which specific mRNA transcripts and
subclasses of mRNAs are impacted by αS accumulation or mutation. Finally, we will investigate
how αS modulates decapping enzymology and composition in a fully in vitro reconstituted system.
We anticipate that this study will reveal that RNA homeostasis disruption is a key aspect of Lewy
body disease pathogenesis and motivate new treatment strategies for ADRD.

## Key facts

- **NIH application ID:** 10890170
- **Project number:** 5R01NS128142-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Vikram Khurana
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $831,256
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890170

## Citation

> US National Institutes of Health, RePORTER application 10890170, Investigating physiologic and pathophysiologic connections between the Parkinson's disease protein alpha-synuclein and RNA binding proteins (5R01NS128142-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10890170. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*