# Role of presynaptic targeting of alpha-synuclein in the pathogenesis of Parkinson's Disease and Dementia with Lewy Bodies

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $371,250

## Abstract

Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB) are characterized by cytoplasmic inclusions
called Lewy Bodies and Lewy Neurites which are composed primarily of α-synuclein (α-syn). Multiple lines of
evidence suggest that these inclusions contribute to disease pathogenesis. Thus, preventing α-syn
aggregation is a critical therapeutic target for preventing disease progression. Normally, α-syn resides at the
presynaptic terminal, preferentially associates with synaptic vesicles, and interaction of α-syn with membranes
inhibit its aggregation. Our proposed study seeks to determine how presynaptic targeting of α-syn prevents it
from converting to a pathologic, aggregation prone form and how PD risk factors disrupt the normal localization
of α-syn and increase its propensity to forming inclusions. Mutations in leucine rich repeat kinase (LRRK2) are
the most common cause of familial Parkinson’s disease. We showed that the G2019S-LRRK2 mutations
increase the formation of α-syn inclusions and that LRRK2 kinase inhibitors reduce inclusion formation, but the
mechanisms by which LRRK2 controls the propensity of α-syn to form aggregates is unknown. Although
current research focuses on the role of LRRK2 in degradative organelles, LRRK2 has also been functionally
implicated at the presynaptic terminal and may play a role in α-syn presynaptic membrane targeting. Recently,
a subset of Rab GTPases was identified as LRRK2 substrates. Rabs control distinct steps in membrane
trafficking pathways in the cell. Ten years ago, the Lindquist lab identified the same Rabs (that were recently
shown to be phosphorylated by LRRK2) as protective in models of α-syn toxicity. We will determine if Rabs
phosphorylated by LRRK2 enhance presynaptic targeting of α-syn and prevent α-syn inclusion formation.
Because inclusions localize to multiple brain regions in PD and DLB, we will inject fibrils into the mouse
striatum which produces inclusions in the substantia nigra pars compacta (SNpc), cortex, and amygdala. In
Aim 1, we will determine the extent to which select Rab isoforms influence α-syn presynaptic targeting using
novel AAV vectors to increase Rab expression in the brain or use antisense oligonucleotides (ASOs) to reduce
Rab levels. Immunohistochemistry and biochemistry will be used to determine if expression of these Rabs in
vivo prevents formation of fibril-induced inclusions in multiple brain regions, and loss of dopamine neurons in
the SNpc. In Aim 2, we will identify the Rab effectors in neurons that specify targeting of vesicles containing α-
syn cargo to the presynaptic terminal. Finally, in Aim 3, we will determine if LRRK2 kinase activity prevents
presynaptic targeting of α-syn and if the mislocalization of α-syn in the cell increases its propensity to form
inclusions. We will also determine the extent to which LRRK2 kinase inhibitors and ASOs in preclinical
development enhance presynaptic targeting of α-syn. These studies will open up new research avenu...

## Key facts

- **NIH application ID:** 10110034
- **Project number:** 5R01NS102257-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Laura A. Volpicelli-Daley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $371,250
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10110034

## Citation

> US National Institutes of Health, RePORTER application 10110034, Role of presynaptic targeting of alpha-synuclein in the pathogenesis of Parkinson's Disease and Dementia with Lewy Bodies (5R01NS102257-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10110034. Licensed CC0.

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