Dopamine Signaling in Parkinson's Disease

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Search this pathway for protein information from PhosphoSitePlus^®, our expert-curated knowledge base of protein phosphorylation and other post-translational modifications.

Pathway Description:

Parkinson’s Disease is the most prevalent neurodegenerative movement disorder among people over age 65. Clinically, this disease is characterized by bradykinesia, resting tremors, and rigidity due to loss of dopaminergic neurons within the substania nigra section of the ventral midbrain. In the normal state, release of the neurotransmitter dopamine in the presynaptic neuron results in signaling in the postsynaptic neuron through D1 and D2 type dopamine receptors. D1 receptors signal through G proteins to activate adenylate cyclase, causing cAMP formation and activation of PKA. D2 type receptors block this signaling by inhibiting adenylate cyclase. Parkinson’s Disease can occur through both genetic mutation (familial) and exposure to environmental and neurotoxins (sporadic). Exposure to environmental and neurotoxins can cause mitochondrial oxidative stress and release of reactive oxygen species (ROS), leading to a number of cellular responses including apoptosis and the misfolding of α-synuclein, which can aggregate with itself and other proteins to form cytotoxic Lewy Bodies. Misfolded α-synuclein is normally ubiquitinated by parkin resulting in proteosomal degradation. However, genetic mutations to both α-synuclein and parkin disrupt this pathway and leads to further accumulation into Lewy Bodies. There is also an inflammatory component to this disease, resulting from activation of microglia that cause the release of inflammatory cytokines and cell stress. This microglia activation causes apoptosis via the JNK pathway and by blocking the Akt signaling pathway via REDD1.

Selected Reviews:

• Bossy-Wetzel E, Schwarzenbacher R, Lipton SA (2004) Molecular pathways to neurodegeneration. Nat. Med. 10 Suppl, S2–9.
• Dauer W, Przedborski S (2003) Parkinson's disease: mechanisms and models. Neuron 39(6), 889–909.
• Girault JA, Greengard P (2004) The neurobiology of dopamine signaling. Arch. Neurol. 61(5), 641–4.
• Patten DA, Germain M, Kelly MA, Slack RS (2010) Reactive oxygen species: stuck in the middle of neurodegeneration. J. Alzheimers Dis. 20 Suppl 2, S357–67.
• Wood-Kaczmar A, Gandhi S, Wood NW (2006) Understanding the molecular causes of Parkinson's disease. Trends Mol Med 12(11), 521–8.
• Yasuda T, Mochizuki H (2010) The regulatory role of α-synuclein and parkin in neuronal cell apoptosis; possible implications for the pathogenesis of Parkinson's disease. Apoptosis 15(11), 1312–21.

We would like to thank Prof. Christopher Phiel, The Research Institute at Nationwide Children’s Hospital, Columbus, OH for contributing to this diagram.