Unraveling the mystery of preferential degeneration of midbrain neurons in neurodegenerative diseases

Title Unraveling the mystery of preferential degeneration of midbrain neurons in neurodegenerative diseases
Acronym oxDOPAMINE
Start date 2021-07-01
End date 2026-06-30
Sponsor European Research Council - Starting Grant (ERC-StG)
Institution DZNE Munich

Associated cell lines

Project Description

The identification of numerous genetic forms of Parkinson's disease (PD) has highlighted the importance of mitochondrial and lysosomal pathways in disease pathogenesis. In my recent work, I discovered that oxidized dopamine (DA) and alpha-synuclein serve as key mediators of mitochondrial and lysosomal dysfunction in midbrain DA neurons that preferentially degenerate in PD. It has been well established that cytosolic DA oxidizes to reactive quinones and accumulates in neuromelanin in midbrain neurons, but my data demonstrated that the process of DA oxidation was dramatically increased in disease. Importantly, oxidized DA was detected only in iPSC-derived DA neurons from familial and sporadic PD patients, but not in PD mouse models. This may at least in part explain why preclinical studies in animal models have not translated to clinical trials in PD patients. oxDOPAMINE will go one step beyond and explore the origin and nature of DA oxidation that predisposes human neurons to selective vulnerability and degeneration. Based on my preliminary work and recent genetic data implicating synaptic genes in PD pathogenesis, I hypothesize that defective synaptic DA metabolism and iron dyshomeostasis play a critical role in the oxidation of cytosolic DA early in disease pathogenesis. Since iron participates in the formation of oxidized DA in normal neurons, my project will include the examination of ‘Neurodegeneration with Brain Iron accumulation’ (NBIA) disorders that share pathological hallmarks of iron accumulation and progressive DA neuron degeneration with PD. A unifying feature of these pathogenic mechanisms is that impaired handling of DA contributes to toxicity of DA neurons. oxDOPAMINE will be of broad significance to a large cohort of patients with neurodegenerative diseases as it will advance our understanding of whether restoration of synaptic dysfunction and iron metabolism may prevent midbrain DA neurodegeneration, to represent a potential therapeutic target.