# Functional investigation of the role of TYR mutations and neuromelanin in Parkinson's disease

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2020 · $237,000

## Abstract

Epidemiological studies have long suggested that Parkinson’s disease (PD) and cutaneous malignant
melanoma (CMM) share a mutual genetic background. While genetic studies have predominantly focused on
examining the role of common variants in mediating this shared etiology, our recent study looking at rare
variation showed that a heterozygous loss of function (LOF) tyrosinase (TYR) mutation substantially increases
PD risk in carriers. However, the functional mechanism behind TYR-associated PD risk has yet to be
elucidated. Most of what is known regarding the function of TYR within the brain stems from its well-characterized role in peripheral melanogenesis, however much remains to be confirmed in the context of the
role of TYR in neuromelanin (NM) formation. TYR is believed to drive dopamine (DA) synthesis in the absence
of tyrosine hydroxylase (TH), however the role of TYR and TH in DA biogenesis and oxidation during
development is unknown. NM is undetectable in brains until around the age of 3 years, with age-dependent
accumulation throughout life. NM is known to consist of two chemically distinct types of pigment, eumelanin
(EM) and pheomelanin (PM). PM (pink/yellow) is located at the core of NM, and EM (brown/black) on the
surface, the latter known to prevent oxidative stress by binding to metals, reactive oxygen species (ROS) and
other toxic cellular byproducts. The EM:PM ratio is therefore critical to NM function. A role for TYR in EM
formation has been demonstrated. Using induced pluripotent stem cell (iPSC)-derived substantia nigra (SN)
DA neurons generated from biallelic TYR mutation, CrispR-Cas9 TYR knockout (KO), TYR overexpressing
(OE) and heterozygous TYR LOF mutant PD lines, we will investigate TYR’s role in DA synthesis and oxidation
as well as its function in regulating the EM:PM ratio, and therefore NM production. Disruption of this ratio may
lead to a reduction in binding capacity and an increase in cellular toxicity. Based on our preliminary data, we
hypothesize that TYR drives DA synthesis and oxidation, and NM synthesis during brain development, and that
loss of TYR results in lower EM:PM ratios due to the reduction of EM production which ultimately leads to
dysfunctional NM. We further hypothesize that the increased PD risk associated with heterozygous TYR
mutations is therefore mediated through the accumulation of increased cellular ROS and iron accumulation,
which predispose SN neurons to degeneration. Using microanalytical ultra-performance chromatography
(UPLC), we will then test NM collected from all lines as well as TYR mutation positive PD patient-derived SN
neurons to accurately evaluate the EM:PM ratio and its effect on the binding capacity of NM. We expect that,
while demonstrating that TYR is involved in DA synthesis, DA oxidation and NM biogenesis in an age-dependent manner, our study will provide direct evidence to support our hypothesis that reduced TYR
increases PD risk through the dysregulation of EM. The valid...

## Key facts

- **NIH application ID:** 9976866
- **Project number:** 1R21AG064470-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** DIMITRI KRAINC
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $237,000
- **Award type:** 1
- **Project period:** 2020-09-30 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976866

## Citation

> US National Institutes of Health, RePORTER application 9976866, Functional investigation of the role of TYR mutations and neuromelanin in Parkinson's disease (1R21AG064470-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9976866. Licensed CC0.

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