Beyond the Brain: Exploring the multi-organ axes in Parkinson’s disease pathogenesis

Gut-Brain: Positions gut dysbiosis, barrier leakage, and α-synuclein propagation as early PD triggers via microbial-neural crosstalk. Therapeutic Innovation: Proposes multi-target strategies—gut microbiota modulation, hepatic metabolic optimization, pulmonary anti-inflammatory therapies, and musculoskeletal support—to synergistically slow PD progression and improve prognosis. • This study challenges the brain-centric view of Parkinson’s disease (PD) by defining systemic interactions across six organ-brain axes (lung, liver, heart, muscle, bone, gut). • Lung-Brain: Links lung dysfunction (reduced respiratory capacity, infection risk) to PD motor deficits and inflammation/oxidative stress-mediated neurodegeneration. • Liver-Brain: Identifies impaired hepatic detoxification and drug metabolism as drivers of neurotransmitter imbalance and neuronal damage. • Heart-Brain: Reveals bidirectional PD-cardiovascular ties via neuroendocrine/pumping dysfunction, disrupting cerebral blood flow regulation. • Muscle-Brain: Highlights neuromuscular/metabolic disruptions as core contributors to PD motor symptoms. • Bone-Brain: Confirms bone-derived cytokines (e.g., osteocalcin) as regulators of neurodegeneration and bone metabolism. Parkinson’s Disease (PD), a complex neurodegenerative disorder, is increasingly recognized as a systemic condition involving multi-organ interactions. Emerging evidence highlights roles of organ-brain axes (lung-, liver-, heart-, muscle-, bone-, and gut-brain) in PD pathogenesis. These axes communicate via neural, circulatory, endocrine, and inflammatory pathways, collectively driving neurodegeneration. For example, lung dysfunction in PD involves respiratory impairment and inflammatory signaling, while gut dysbiosis triggers α-synuclein aggregation via the vagus nerve. Such cross-organ interactions underscore PD’s systemic nature, challenging traditional brain-centric models. 1. Decipher mechanisms linking peripheral organs (e.g., lung, gut) to PD via shared pathways. 2. Explore bidirectional organ-brain interactions (e.g., liver metabolism affecting neurotoxin clearance). 3. Propose multi-organ therapeutic strategies targeting integrated signaling networks. Key Scientific Concepts of Review. 1. Lung-Brain Axis: Respiratory dysfunction (motor impairment, inflammation) exacerbates neurodegeneration. 2. Liver-Brain Axis: Metabolic dysregulation alters neurotoxin clearance; drugs (e.g., levodopa) impact liver function. 3. Heart-Brain Axis: Autonomic dysfunction reduces cerebral blood flow; neuroendocrine changes promote α-synuclein pathology. 4. Muscle-Brain Axis: Neuromuscular/metabolic disruptions worsen motor symptoms. 5. Bone-Brain Axis: Bone-derived hormones (osteocalcin, OCN) and inflammation influence cognition. 6. Gut-Brain Axis: Dysbiosis drives α-synuclein misfolding; gut metabolites modulate neuroinflammation. Integrated Mechanisms: Shared pathways (neuroinflammation, oxidative stress) create a regulatory network, suggesting therapies targeting multi-organ crosstalk (e.g., probiotics, anti-inflammatory agents).