4.6 Review

Role of dopamine in the pathophysiology of Parkinson's disease

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Summary: Neurons that accumulate the highest levels of neuromelanin with age are also the most susceptible to degeneration in Parkinson's disease. Using a neuromelanin-producing rat model, Gonzalez-Sepulveda, Compte et al. show that slowing down age-dependent neuromelanin production can help prevent Parkinson's disease-like features.
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DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson's disease

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Summary: Dopamine dyshomeostasis is recognized as a key factor in the degeneration of nigrostriatal neurons in Parkinson's disease (PD). It has been found that the levels of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) increase in experimental models and postmortem PD patients, leading to modifications of the presynaptic protein alpha Synuclein (alpha Syn). This modification triggers alpha Syn accumulation and impairs its clearance, resulting in neuronal dysfunction and motor impairment. The development of a specific antibody that detects DOPAL-modified alpha Syn in human brain tissues further supports the relevance of this interaction in PD neurodegeneration.

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Summary: Global studies show that except for G2019S, most of the LRRK2 variants are not common in majority of countries, with G2385R and R1628P primarily found in East Asian countries. Estimates adjusted for ethno-racial composition are generally lower than crude estimates, suggesting that clinic-based studies may overstate the true prevalence of some LRRK2 variants in Parkinson's disease.

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The role of tyrosine hydroxylase-dopamine pathway in Parkinson's disease pathogenesis

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Summary: This study found that the TH-DA pathway plays a critical role in the pathogenesis of Parkinson's disease. LRRK2 and PINK1 have opposing effects on the TH-DA pathway, and the balance between them affects the survival of DA neurons. Mutations in LRRK2 or PINK1 can disrupt this balance, leading to the demise of DA neurons.

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Impairment of neuronal mitochondrial function by l-DOPA in the absence of oxygen-dependent auto-oxidation and oxidative cell damage

Philipp Hoermann et al.

Summary: l-DOPA, the most commonly used drug for treating symptoms of Parkinson's disease, can be enzymatically converted to dopamine to restore depleted neurotransmitter levels. Research has shown that oxygen tensions comparable to those in the mammalian brain can significantly inhibit l-DOPA auto-oxidation and even enhance its ability to scavenge reactive oxygen species. This study further revealed that l-DOPA reprograms mitochondrial metabolism, reducing oxidative phosphorylation and inducing reductive glutamine metabolism, shedding new light on its cellular effects and neuro-toxicity under physiological oxygen levels.

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Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites

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Enhanced tyrosine hydroxylase activity induces oxidative stress, causes accumulation of autotoxic catecholamine metabolites, and augments amphetamine effects in vivo

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DJ-1 inhibits microglial activation and protects dopaminergic neurons in vitro and in vivo through interacting with microglial p65

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