# BTBD9, a novel regulator of manganese-induced neurotoxicity

> **NIH NIH R21** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $251,813

## Abstract

Project Summary:
Manganese (Mn) is an essential metal, but excess exposure is associated with increased risk for Parkinson's
disease (PD). Restless legs syndrome (RLS) is a common neurological disorder seen in ~10% of the US
population. The pathobiology of RLS has been linked to deficits in dopaminergic (DAergic) function and Fe
deficiency. Interestingly, increased prevalence of PD is noted in RLS, and vice versa. BTBD9 is one of the
genetic risk factors for RLS. Fe-deficiency is associated with increased brain deposition of Mn, and Mn shares
numerous homeostatic and transport pathways with Fe, suggesting that concentrations of another metal, such
as Mn, may opportunistically increase upon Fe deficiency. Given the established link between Fe and Mn
biology, we propose to evaluate whether BTBD9 may regulate Mn-induced cytotoxicity and DAergic
neurodegeneration. Furthermore, in vivo evidence has linked insulin/insulin-like growth factor (IGF) signaling
with both Mn biology and RLS. Mn-deficiency caused glucose intolerance and reduced insulin production,
while Mn toxicity caused reduced ATP and insulin/IGF receptor expression. Meanwhile, patients with diabetes
have significantly increased risk to develop RLS than non-diabetic groups. These observations support links
between (1) Mn neurotoxicity, (2) DA neurobiology/ parkinsonism, (3) RLS, and (4) IGF signaling. However, we
lack a mechanistic basis for the direct targets of Mn neurotoxicity in IGF signaling networks and the role DA
neurobiology plays in these mechanisms. Here, we propose a direct protein target (BTBD9) regulating IGF
signaling to protect against oxidative stress and mitochondrial dysfunction induced by Mn exposure, thus
protecting DAergic function. We will use the Caenorhabditis elegans (C. elegans) model as it shares a highly
conserved neurogenetic architecture and IGF signaling components with mammalians. Our preliminary data
established the requisite technology and conceptual basis for this proposal. Our hypothesis will be tested in the
following Specific Aims:!Specific Aim 1. Investigate the protective mechanism of BTBD9/HPO-9 against
Mn-induced toxicity and its role in IGF signaling in C. elegans. We will verify whether HPO-9 moderates
oxidative stress, mitochondrial mass, membrane potential, ATP production and how it regulates the IGF
signaling upon Mn exposure. Specific Aim 2. Determine if HPO-9 modulates Mn-induced DAergic
neurotoxicity via IGF signaling in C. elegans. We will assess DAergic neurodegeneration, DA-dependent
behavior and DA concentrations in worms upon Mn exposure. Results from this study will have a broad clinical
and translational impact. Our scientific approach will (1) reveal if systemic and/or neuronal alterations in Mn
may contribute to the impaired DAergic function seen in RLS (2) establish a functional link between Mn
biology, DAergic functionality and IGF signaling 3) provide a new target protein for therapeutic interventions to
ameliorate oxidative st...

## Key facts

- **NIH application ID:** 10055864
- **Project number:** 1R21ES031315-01A1
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Pandy Chen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $251,813
- **Award type:** 1
- **Project period:** 2020-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10055864

## Citation

> US National Institutes of Health, RePORTER application 10055864, BTBD9, a novel regulator of manganese-induced neurotoxicity (1R21ES031315-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10055864. Licensed CC0.

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