# Dnajc13 p.N860S as a physiologic model ofalpha-Synuclein overexpression

> **NIH NIH R21** · UNIVERSITY OF FLORIDA · 2024 · $190,625

## Abstract

PROJECT SUMMARY/ABSTRACT
Parkinson’s disease (PD) is a debilitating neurodegenerative disorder associated with the loss of dopamine
producing neurons and the accumulation of protein aggregates rich in α-synuclein (Lewy bodies). While the
causes of PD are not fully known, rare families with monogenic forms provide translatable targets and the models
in which to test novel therapeutic strategies. For example, α-synuclein (SNCA) was discovered to be the major
protein constituent of Lewy bodies only after the gene encoding it was linked to familial PD. Our discovery of
SNCA multiplications subsequently provided the rationale and models to develop multiple approaches to lower
αSyn expression that are currently in clinical trials. In 2014, we genetically linked a missense mutation (p.N855S)
in DNAJC13 (encoding receptor-mediated endocytosis-8; RME-8) to late-onset autosomal-dominant
parkinsonism in multi-incident Mennonite kindreds (RME-8 PD). Affected family members had post-mortem Lewy
pathology rich in α-synuclein (αSyn) and neuronal loss in the substantia nigra (SNpc). RME-8 is a DNAJ-domain-
containing protein that, together with heat shock cognate 70 (Hsc70), stimulates: 1) the refolding of misfolded
proteins and; 2) clathrin removal from vesicles. Hence, loss of RME-8 leads to an accumulation of clathrin coated
vesicles, hyper extended membrane tubules and the aggregation of cargos. Given this background, we
developed a Dnajc13 p. N860S knock-in (DKIHet; corresponding to human p. N855S mutation) mouse model.
Preliminary studies in DKIHet brain at 3 months of age reveal the RME-8 mutation: 1) increases soluble monomeric
αSyn and clathrin coated intermediates; 2) causes synaptic delay following repetitive stimulation, and; 3) impairs
movement initiation (resulting in freezing) in open field behavior. The phenotypes DKIHet confers are consistent
with a pathologic gain of function and reminiscent of a ‘synaptopathy. In this proposal we aim to more fully
characterize the DKIHet model with respect to mutant and wildtype RME-8 protein-binding in synaptosomes from
microdissected striatum. We will more fully characterize differences in αSyn biology, including phosphorylated
and higher molecular weight species. We will also look at the mutation’s impact on dopaminergic function,
including biochemical, physiologic and morphologic assessments. Lastly, given RME-8 is also an interferon-
responsive gene we will explore neuroimmune biology and focus on microglial pruning of dopaminergic
terminals. Completion of these experiments will define the biologic role of DNAJC13 p.N855S, highlight its
mechanism of action in disease pathogenesis, and demonstrate the utility of DKIHet mice.

## Key facts

- **NIH application ID:** 10789102
- **Project number:** 1R21NS135376-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** MATTHEW J FARRER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $190,625
- **Award type:** 1
- **Project period:** 2024-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789102

## Citation

> US National Institutes of Health, RePORTER application 10789102, Dnajc13 p.N860S as a physiologic model ofalpha-Synuclein overexpression (1R21NS135376-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10789102. Licensed CC0.

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