Neuronal design and determinants of selective neuronal vulnerability of dopaminergic neurons in Parkinson's disease

• Published in: Handbook of Behavioral Neuroscience Vol. 32; pp. 409 - 427
• Main Authors: Zampese, Enrico, Moran, James, Surmeier, D. James
• Format: Book Chapter
• Language: English
• Published: Elsevier Science & Technology 2025
• Subjects: Aging; Bioenergetic; Ca2; Dopamine; Mitochondria; Neurodegeneration; Parkinson's disease; Mitochondria; Dopamine; Parkinson's disease; Neurodegeneration; Ca2; Aging; Bioenergetic
• ISBN: 9780443298677; 044329867X
• ISSN: 1569-7339
• DOI: 10.1016/B978-0-443-29867-7.00039-6

The cardinal motor symptoms of Parkinson's disease (PD) are a consequence of the degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons. Why these neurons are selectively vulnerable in PD has been the subject of debate and discussion for decades. Given the absence of a broader brain pathology at the time when SNc dopaminergic neurons begin to be lost, it is reasonable to assume that cell autonomous factors contribute to pathogenesis. Here, the evidence linking the unusual anatomical and physiological features of SNc dopaminergic neurons to their selective vulnerability is reviewed. The design of these neurons undoubtedly creates both proteostatic and bioenergetic challenges. To meet the bioenergetic challenge, SNc dopaminergic neurons link spiking to stimulation of mitochondrial oxidative phosphorylation through a feedforward signaling pathway. Although this adaptation allows neurons to meet their bioenergetic needs, it comes at the cost of elevated oxidant stress. The linkage between oxidant stress, loss of mitochondrial function with aging, genetic mutations associated with PD and PD pathogenesis is discussed. The potential linkage between mitochondrial dysfunction and synucleinopathy also is explored. Lastly, the translational implications of the bioenergetic adaptations in SNc dopaminergic neurons is summarized.