Dopamine Signaling in Parkinson's Disease

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• Reviews
• Pathway Key
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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 results in mitochondrial oxidative stress and release of reactive oxygen species (ROS), which leads 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 result in 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.
• Kuan CY, Burke RE (2005) Targeting the JNK signaling pathway for stroke and Parkinson's diseases therapy. Curr Drug Targets CNS Neurol Disord 4(1), 63–7.
• Wood-Kaczmar A, Gandhi S, Wood NW (2006) Understanding the molecular causes of Parkinson's disease. Trends Mol Med 12(11), 521–8.