# Impact of Dysfunctional BDNF on Dopamine Terminal Remodeling in the Parkinsonian Striatum

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2020 · $404,677

## Abstract

While there are a number of therapeutic options for individuals with Parkinson's disease (PD) these therapies
do not work uniformly well in all patients. Indeed, a recent retrospective analysis of the ELLDOPA study
reported that early-stage PD subjects receiving equivalent levodopa doses experienced a magnitude of
response ranging from a 100% improvement to a 242% worsening as assessed with the United Parkinson's
Disease Rating Scale part III (UPDRS-III, motor subscore). This example underscores the incredible
heterogeneity in clinical response to standard-of-care anti-parkinsonian therapy, even when disease severity is
taken into account. Similar findings have been reported over the past several decades for the experimental
regenerative approach of neural grafting. While some PD patients have shown marked and lasting benefit
following engraftment of primary dopamine (DA) neurons, many have also shown no or limited benefit. Recent
preclinical data in aged parkinsonian rats together with that from two milestone clinical reports provide
compelling and sobering data demonstrating that even when robust survival of grafted DA neurons and
extensive neurite outgrowth is achieved, obstacle(s) remain that interfere with functional circuit restoration
within the aged, parkinsonian brain. As clinical grafting trials are reemerging, it remains uncertain what specific
risk factors negatively impact clinical responsiveness to DA terminal remodeling. In attempt to deconstructing
the complexity of PD and response to therapy, we recently identified one candidate genetic variant, with
prevalence of up to 40% in the human population, which may prove useful in this regard; specifically, a
functional single nucleotide polymorphism (SNP) rs6265 in the Bdnf gene for brain-derived neurotrophic factor
(BDNF) that results in dysfunctional BDNF release. We have recently observed diminished therapeutic efficacy
of oral levodopa in two distinct cohorts of PD patients with this SNP risk allele. In the current application we
propose to test the hypothesis that this risk allele also underlies the variability in clinical response to DA neuron
grafting in PD patients. Specifically, we hypothesize that BDNF is an unrecognized contributor to the
discordant finding of abundant survival of grafted DA neurons and lack of behavioral efficacy reported in a
subpopulation of PD patients and in association with normal aging in parkinsonian rats. In this application we
propose three Specific Aims to test the overarching hypothesis that impaired BDNF signaling, either through
this common SNP and/or advanced age, is a key factor in limiting functional DA terminal remodeling. Toward
this end, we have generated a knock-in rat model of the human rs6265 BDNF variant and propose to use this
novel tool to characterize its effects and interaction with aging and DA-depletion on the function and synaptic
integration of new DA terminals in the parkinsonian striatum using neural grafting as a model syst...

## Key facts

- **NIH application ID:** 9838825
- **Project number:** 5R01NS105826-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** KATHY STEECE-COLLIER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $404,677
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838825

## Citation

> US National Institutes of Health, RePORTER application 9838825, Impact of Dysfunctional BDNF on Dopamine Terminal Remodeling in the Parkinsonian Striatum (5R01NS105826-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838825. Licensed CC0.

---

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