# Role of pathogenic Parkinsonian mutations in the seeding and propagation of alpha-synuclein in the CNS

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2021 · $413,108

## Abstract

Abstract
 The etiology of Parkinson’s disease is multivariate, ranging from identified genetic mutations to
strict environmental causation. So far, more than 18 genes have been identified that result in parkinsonism.
The two most common genetic mutations that lead to parkinsonism are: 1) mutations in the GBA gene that
encodes the glucocerebrosidase protein, and 2) mutations in the LRRK2 gene that Leucine Rich Repeat
Kinase II protein. In addition to their known “genetic i.e familial” relationship to disease causation, both
the GBA and LRRK2 genes are also considered to be “risk factors” for development of PD, in that not
everyone with these mutations develops Parkinson’s disease and they may only manifest after a second
“hit”. No matter the initiating cause of PD, almost all cases of Parkinson’s disease share common aspects
of pathology, including: 1) the presence of aggregated alpha-synuclein, 2) loss of SNpc DA neurons and 3)
an increase in neuroinflammation. Additionally, one also sees cognitive and motor output changes. In this
application, the we will examine different pathological mechanisms known to initiate Parkinson’s disease,
including protein kinase activation, protein management or inflammation will alter/affect the aggregation
and spread of α-syn throughout the nervous system. Specifically, we will examine the effect on PD
pathophysiology including SNpc DA neuron loss, loss of basal ganglia catecholamines, induction of
neuroinflammation and spread of misfolded alpha-synuclein. We will also examine if cognitive and motor
behavioral changes occur in these 3 conditions after PFF seeding. These parkinsonian pathologies will be
examined following injection of preformed filaments of alpha-synuclein (PFFs) into three different regions
of the CNS, including two known to be involved in PD (olfactory bulb and striatum) and one that is not
(internal control, hippocampus). In Specific Aim 1, we will examine if PFFs injected into different regions
of the CNS of mice carrying a G2019S mutation in the LRRK2 gene alter the seeding and spread of α-Syn
as well as alter other known pathologies in PD as described above. In Specific Aim 2, we will examine if
preformed fibrils of alpha-synuclein (PFFs) injected into different regions of the CNS of mice carrying a
L444P GBA mutation alters the seeding and spread of α-Syn as well as alter other known pathologies in
PD as described above. In Specific Aim 3 we will test the hypothesis that a prior neuroinflammatory insult
(infection with the H1N1 influenza virus) to the brain will increase the seeding and spread of PFFs in mice
carrying PD susceptibility genes as well as alter other known pathologies in PD as described above. These
three aims will allow us to determine if any one or more of these pathological mechanisms (kinase activation
(genetic), protein mishandling (gene x environment” or viral infection (environment) directly influence the
spread of misfolded alpha-synuclein and other common parkinsonian...

## Key facts

- **NIH application ID:** 10145089
- **Project number:** 5R01NS110084-03
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** RICHARD J SMEYNE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $413,108
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145089

## Citation

> US National Institutes of Health, RePORTER application 10145089, Role of pathogenic Parkinsonian mutations in the seeding and propagation of alpha-synuclein in the CNS (5R01NS110084-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145089. Licensed CC0.

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