At Death's Door: Cytosolic Dopamine in Patients With Parkinson Disease

Abstract

Parkinson disease (PD) is a progressive neurodegenerative disorder pathologically characterized by neuronal accumulation of phosyphorylated α-synuclein (p-α-syn) aggregates. Cardinal signs of PD (tremor, rigidity, and bradykinesia) are predominantly due to loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Dopaminergic therapies remain the cornerstone of PD management and include levodopa, monoamine oxidase inhibitors, and dopamine agonists. In the cytosol, dopamine is synthesized from l-dopa (levodopa) by L-aromatic-amino-acid decarboxylase (LAAAD). Vesicular monoamine transporter 2 (VMAT2) transports dopamine from the cytosol into synaptic vesicles. Once within vesicles, dopamine is protected from degradation and oxygenation. In healthy brains, most intracellular dopamine, typically 90%–95%, is stored in vesicles.1 Owing to active transfer, the vesicular concentration of dopamine is much higher than the cytoplasmic concentration. Dopamine within synaptic vesicles may reach concentrations of 500 mM, while cytoplasmic concentrations are in the low µM range. As such, vesicular dopamine is concentrated over 30, 000-fold compared with cytoplasmic dopamine.

Publication Title

Neurology

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