THE INFLUENCE OF HOMOCYSTEINE AND THE GUT-BRAIN AXIS ON MOTOR FUNCTION AND NEUROMUSCULAR ADAPTATION IN PARKINSON’S DISEASE: IMPLICATIONS FOR PHYSICAL ACTIVITY AND REHABILITATION

Abstract

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of α-synuclein (α-syn) in the substantia nigra, leading to both motor and non-motor dysfunctions. While PD primarily manifests as a movement disorder, increasing evidence suggests that gastrointestinal (GIT) dysfunction and systemic metabolic disturbances play a crucial role in its progression. Elevated homocysteine (Hcy) levels, often observed in PD patients due to genetic factors, L-dopa therapy, malnutrition, age, and sex, have been linked to accelerated neurodegeneration, vascular inflammation, and impaired neuromuscular function, potentially exacerbating disease symptoms and affecting physical performance and rehabilitation outcomes. Objective: This review examines the role of hyperhomocysteinemia (HHcy) in gut-brain axis dysfunction, its impact on intestinal microbiota, inflammatory responses, and α-synuclein aggregation, and its potential consequences for neuromuscular adaptation, motor control, and physical rehabilitation in PD patients. Methods: A comprehensive analysis of existing literature was conducted to explore the association between HHcy, intestinal dysbiosis, microvascular dysfunction, and neuroinflammation in PD. Special emphasis was placed on how Hcy-related metabolic disturbances influence physical function, gait stability, and rehabilitation potential in PD patients. Results: Findings suggest that elevated Hcy levels contribute to intestinal flora dysregulation, increased inflammation, and microvascular impairment, which may further exacerbate dopaminergic neurodegeneration and neuromuscular dysfunction. Additionally, HHcy-induced systemic inflammation and gut microbiome disturbances appear to aggravate neuroinflammation through the gut-brain axis, potentially worsening motor impairments and reducing adaptability to physical therapy and exercise interventions. Given that exercise and targeted rehabilitation programs are crucial in maintaining mobility, muscle coordination, and neuromuscular function in PD, understanding the metabolic role of Hcy can inform novel therapeutic strategies to enhance physical resilience and motor performance in PD patients. Conclusions: HHcy is a critical metabolic factor that influences both neurodegeneration and motor function deterioration in PD, with significant implications for rehabilitation, exercise capacity, and neuromuscular adaptation. Future research should focus on developing targeted interventions, including dietary strategies, pharmacological treatments, and structured exercise programs, to mitigate the effects of HHcy on both the gut-brain axis and motor function. Integrating nutritional and physical activity-based interventions may provide a more comprehensive approach to PD management, improving functional outcomes, mobility, and overall quality of life in affected individuals.