Convergent Vulnerability and Divergent Outcomes of the Dopaminergic System in Parkinson's and Alzheimer's Diseases.

Authors

Yu-Ting Xi, Chen-Xi Jia, Hui-Dan Wang, Pei-Yao Liu, Peng Li, Qianqian Niu, Ya-Ling Yin

Published in

Ageing research reviews. Pages 103358. Sep 06, 2026. Epub Sep 06, 2026.

Abstract

Dopaminergic neurons constitute a heterogeneous neuronal system that regulates diverse brain functions, whereas distinct dopaminergic neuronal subpopulations exhibit unique intrinsic biological properties, selective vulnerability, and disease-specific pathological trajectories across neurodegenerative disorders. Parkinson's disease (PD) is characterized by the progressive degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons, whereas Alzheimer's disease (AD) predominantly involves progressive dysfunction of ventral tegmental area (VTA)-associated dopaminergic circuits rather than widespread dopaminergic neuronal loss. This review provides a comprehensive overview of the regional heterogeneity of SNc and VTA dopaminergic neurons across multiple dimensions, including anatomical organization, electrophysiological properties, Ca²⁺ homeostasis, bioenergetics, dopamine metabolism, and proteostasis, and discusses how these cell-autonomous characteristics collectively shape the intrinsic vulnerability of distinct dopaminergic neuronal subpopulations. Furthermore, it discusses how intrinsic vulnerability interacts with disease-associated pathological processes to drive the divergent pathological trajectories of the dopaminergic system, culminating in selective neuronal degeneration in PD and progressive dysfunction of VTA-associated neural circuits in AD. Building on this evidence, this review proposes a conceptual framework in which the pathological fate of the dopaminergic system is shaped by the interplay between intrinsic vulnerability and circuit dependency. Building upon this framework, the review further discusses disease-modifying strategies and their translational implications for PD and AD. This conceptual framework provides an integrated perspective for understanding the divergent pathological trajectories of the dopaminergic system in PD and AD and establishes a foundation for future hypothesis-driven studies on neuronal subtype-specific vulnerability.

PMID:
42702294
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.

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