Neuro-Endocrine Crosstalk in Parkinson's Disease: From Mechanistic Insights to Precision Endocrinology

Abstract:

Parkinson’s disease (PD) is a complex neurodegenerative disorder whose pathogenesis extends far beyond the traditional framework of dopaminergic neuronal loss in the substantia nigra. Growing evidence increasingly implicates neuro-endocrine crosstalk as a central contributor to PD pathophysiology. This review aims to systematically elucidate the pivotal role of neuro-endocrine interactions in PD, spanning the continuum from molecular mechanisms to precision endocrine interventions. The core sections explore how dysregulation of the hypothalamic-pituitary-adrenal axis, insulin resistance, impaired leptin signaling, sex hormone imbalance, vitamin D deficiency, and thyroid dysfunction collectively accelerate neurodegenerative progression and contribute to both motor and non-motor manifestations of PD. In addition, chronic inflammation, oxidative stress, mitochondrial dysfunction, and abnormal energy metabolism are discussed as key mechanisms linking endocrine disturbance with neuronal vulnerability and α-synuclein pathology. Furthermore, the review emphasizes the reciprocal effects of PD pathology on endocrine function, including α-synuclein aggregation in autonomic and hypothalamic nuclei that leads to sympathetic and vagal neuropathy, melatonin reduction, circadian rhythm disruption, and broader systemic endocrine abnormalities. Building on these mechanistic insights, we highlight emerging precision-endocrine strategies such as the development of multimodal biomarkers, targeted modulation of metabolic and circadian pathways, and Artificial Intelligence-driven personalized therapeutic designs. Finally, this article examines key translational challenges, including limitations of current models, clinical trial design, target selectivity, inter-individual variability, blood-brain-barrier permeability, and long-term safety and efficacy monitoring. It also outlines future directions for translating precision endocrinology into more effective PD prevention, diagnosis, and therapy (Graphical Abstract).