Respiratory control dysfunction and vulnerability in Parkinson's disease

Respiratory dysfunction is increasingly recognized as a clinically relevant yet underexplored feature of neurodegenerative diseases, particularly Parkinson's disease (PD). Although traditionally defined by motor symptoms resulting from dopaminergic degeneration, PD also affects neural systems involved in autonomic and respiratory control. Clinical and experimental evidence demonstrates that respiratory impairments in PD include alterations in respiratory rhythm generation, chemosensitivity, ventilatory responses to hypoxia and hypercapnia, and sleep-related breathing regulation. Emerging data indicate that these disturbances are not merely secondary consequences of motor dysfunction, but instead reflect selective vulnerability of brainstem respiratory networks. In this review, we discuss current evidence from human studies and experimental models, with emphasis on circuit-level mechanisms underlying respiratory dysfunction in PD. We highlight how oxidative stress, neuroinflammation, and neuromodulatory alterations contribute to degeneration and dysfunction of respiratory-related nuclei. We further examine the complex interactions between chemosensory control, sleep-wake regulation, and respiratory stability, as well as compensatory mechanisms that may partially preserve ventilatory function during disease progression. Finally, we discuss potential treatments for these dysfunctions, as well as major conceptual gaps and controversies in the field, including species-dependent differences, limitations of current experimental models, and challenges in translating mechanistic findings into clinical interventions. We propose that respiratory control networks represent a mechanistically relevant and selectively vulnerable system in PD, with important implications for early diagnosis, biomarker discovery, and the development of targeted therapeutic strategies.