Friday, April 4, 2025
4/4/2025
Influence of neuromelanin on single dopaminergic neurons in Parkinson's disease. - Dopamine neurons in the substantia nigra pars compacta (SNc) are exquisitely susceptible to degeneration and are responsible for the cardinal motor symptoms of Parkinson’s disease (PD). All currently available treatments for PD such as L-DOPA focus on symptoms, and none of the promising results from preclinical studies have translated to a single disease-modifying therapeutic agent. In humans, catecholaminergic neurons, including dopamine neurons in the SNc, specifically express the dark brown pigment neuromelanin and are among the most sensitive neurons to degeneration in PD. Neuromelanin accumulation is not observed in rats and mice, thus the cellular and systemic effects of neuromelanin accumulation in dopamine neurons are not currently understood. We have recently developed and validated the first Cre-dependent adeno-associated virus (AAV-DIO-hTyr) that can be used to express the human tyrosinase enzyme specifically in dopamine neurons of dopamine transporter (DAT)-Cre mice. Preliminary results indicate that following virus injection, dopamine neurons progressively accumulate neuromelanin, producing disrupted cellular physiology, PD-like motor impairment, and ultimately catastrophic dopamine neuron cell death. This project will leverage the expertise of three established labs with deep experience studying neurodegenerative disease, catecholaminergic neurons, electrophysiology, and neuroinflammation to explore neuromelanin accumulation in this novel mouse model. The hypothesis to be tested is that progressive neuromelanin accumulation disrupts cellular physiology, neuritic morphology, behavior, and ultimately causes neuroinflammation and cell death. Experiments in Aim 1 will delineate the anatomical and behavioral consequences of neuromelanin accumulation in dopamine neurons from mice that have and have not been exposed to L-DOPA. Experiments in Aim 2 will use patch clamp electrophysiology to determine the effects of neuromelanin on neuronal excitability in the SNc and the adjacent ventral tegmental area (VTA), which is somewhat protected in PD. Results will be assessed by time point and level of neuromelanin accumulation in single neurons. Experiments in Aim 3 will use Patch-sequencing to correlate electrophysiological findings with molecular phenotypes in single dopamine neurons following neuromelanin accumulation and L-DOPA treatment. Astrocyte and microglia will be also tested for inflammatory and disease-related phenotypes in the midbrain and also the striatum, the main terminal field of dopamine neurons. Results will be compared to other models and postmortem data from PD patients. These studies will be the first to explore the distinct factors introduced by neuromelanin accumulation and L-DOPA treatment in mouse dopamine neurons. Results will fill a key knowledge gap in the PD field and inform ongoing and future studies into PD pathogenesis that could be transformative.
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