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Parkinson's Disease Signaling

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D2-type D1-type D2-type D1-type cAMP CDK5 Transcription Post-Synaptic Signaling Blocked Neurodegeneration Ca 2+ Na + PKA PP1 DARPP-32 DARPP-32 AC Gα s Gα i β,γ β,γ AMPAR NMDAR AMPAR NMDAR Dopamine Synaptic Vesicle Dopa Decarboxylase Tyrosine L-DOPA Tyrosine Hydroxylase Akt Cell Survival ROS LRRK2 Mutation PINK1 Mutation Lewy Body Aggregation Proteosomal Degradation α-Synuclein α-Synuclein SNARE ComplexMitochondria GREEN Text = Healthy RED Text = Stress, Aggregation ORANGE Text = Parkinson’s Disease Apopto-sis α-Synuclein Monomer Key Healthy Parkinson’s Disease JNK MKK4/7 mTORC2 Cell Stress, Cytokines Environmental Toxins, Neurotoxins Dopamine Misfolding REDD1 Dopamine Metabolism DJ-1 PINK1 Parkin SNARE Complex Assembly/Clustering VAMP2 SNAP25 Syntaxin1 CREB CREM ATF α-Synuclein Dopamine Signaling Genetic Mutations Lysosomal Processing Mitochondrial Dysfunction α-Synuclein- mediated ER Stress α-Synuclein Aggregation & Phosphorylation rev. 10/2/24

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Parkinson’s disease (PD) is the second most common neurodegenerative disease. As such, PD is characterized by incurable progressive motor deterioration driven by the loss of dopamine-producing neurons in the brain, which is associated with cell death within the substantia nigra section of the ventral midbrain.1

In dopamine signaling in healthy individuals, tyrosine hydroxylase catalyzes the conversion of tyrosine to levodopa (L-DOPA), which dopa decarboxylase further converts to dopamine.2 Dopamine is stored in the synaptic vesicle, and α-synuclein (α-syn) drives the assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein complexes at the neuronal synapse to facilitate the fusion of dopamine-containing synaptic vesicles.3–5 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 cyclic adenosine 3′,5′-monophosphate (cAMP) formation and activation of protein kinase A (PKA).5 D2-type receptors block this signaling by inhibiting adenylate cyclase.

In individuals with PD, this process is disrupted. PD may be driven by, environmental toxins, neurotoxins, or genetic mutations, all of which can alter cell biology in numerous ways. Importantly, while PD can be genetic in origin, only 10-20% of cases are monogenic PD, and most cases are idiopathic.2 In PD, dopamine accrues within the neuron, becoming metabolized and producing reactive oxygen species (ROS). Simultaneously, normal mitochondrial function is inhibited, also resulting in ROS production. Excess ROS increases apoptosis and influences α-syn misfolding, which leads to the accumulation of large, abnormal protein aggregates called Lewy bodies in the neuron. The Lewy bodies impede dopamine signaling and ultimately drive neuronal death. Thus, mitochondrial dysfunction and protein aggregation in dopaminergic neurons may be responsible for premature neuronic degeneration.

Through the study of genetic PD, at least 90 genes have been suggested to be linked to PD pathogenesis. These genes include leucine-rich repeat kinase 2 (LRRK2), the most common genetic cause for PD,6 and α-syn, which is fundamental to PD biology.4 Recessively inherited loss-of-function mutations in parkin, protein deglycase DJ-1 (DJ-1), and PTEN induced putative kinase 1 (PINK1) cause mitochondrial dysfunction and accumulation of ROS, whereas dominantly inherited missense mutations in α-syn and LRRK2 may affect protein degradation pathways, leading to protein aggregation and accumulation of Lewy bodies. Another common feature of the mutations in α-syn, Parkin, DJ-1, PINK1, and LRRK2 is impaired dopamine release and dopaminergic neurotransmission, which may be an early pathogenic precursor prior to death of dopaminergic neurons.

Thus, four conditions that are central to PD pathology include dysfunction in lysosomal processing, mitochondrial dysfunction, α-syn-mediated endoplasmic reticulum (ER) stress, and α-syn aggregation and phosphorylation.

Selected Reviews:

1. Surmeier, DJ. Determinants of dopaminergic neuron loss in Parkinson’s disease. FEBS J 285, 3657 (2018).

2. Bandres-Ciga, S, Diez-Fairen, M, Kim, JJ, et al. Genetics of Parkinson’s disease: An introspection of its journey towards precision medicine. Neurobiol Dis 137, 104782 (2020).

3. Sivakumar, P, Nagashanmugam, KB, Priyatharshni, S, et al. Review on the interactions between dopamine metabolites and α-Synuclein in causing Parkinson’s disease. Neurochem Int 162, 105461 (2023).

4. Panicker, N, Ge, P, Dawson, VL, et al. The cell biology of Parkinson’s disease. J Cell Biol 220, (2021).

5. Smith, PD, O’Hare, MJ & Park, DS. CDKs: Taking on a role as mediators of dopaminergic loss in Parkinson’s disease. Trends Mol Med 10, 445–451 (2004).

6. Madureira, M, Connor-Robson, N & Wade-Martins, R. “LRRK2: Autophagy and Lysosomal Activity”. Front Neurosci 14, 536324 (2020).

created November 2009

revised September 2012

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