Therapeutic Mechanisms of Exercise in Parkinson's Disease

Abstract

Despite being the second-most common neurodegenerative disease, the etiology of Parkinson's disease (PD) remains uncertain with current knowledge suggestive of multiple risk factors. Furthermore, curative treatment does not yet exist, and treatment is primarily symptomatic in nature. For this reason, supportive therapies such as exercise are a crucial tool in PD management. It is useful to better understand how exercise affects the brain and body in the context of PD to guide clinical decision-making and determine the optimal exercise intensity and modality for PD patients. This review outlines the various mechanisms by which exercise can be beneficial as a therapeutic option in PD.

Keywords: Parkinson’s disease; exercise; management; mechanism.

Figure 1

Schematic figure outlining the pathophysiological mechanisms in Parkinson’s disease (PD) that are modulated by exercise. (A) Pathological beta waves and synchronization of neural oscillations on electroencephalography can be reduced by exercise. (B) Both macroscopic and microscopic vessel perfusion is decreased in PD, and exercise can restore perfusion. (C) Gut dysbiosis is a proposed contributor to PD etiology, leading to decreased levels of beneficial short-chain fatty acids (SCFAs) such as butyrate; exercise can increase both butyrate and butyrate-producing bacteria. (D) Exercise reverses the effects of mitochondrial dysfunction and acts via nuclear factor erythroid2-related factor 2 (Nrf2) to increase glutathione peroxidase (GPX4) levels and restore the glutathione-to-glutathione disulfide ratio (GSH/GSSG), resulting in reduced oxidative damage. (E) Exercise can increase the levels of protective neurotrophic factors in the brain, including brain-derived neurotrophic factor (BDNF), which acts on tropomyosin-related kinase B (TrkB) receptors, glial cell line-derived neurotrophic factor (GDNF), which acts on rearranged during transfection (RET) receptors, and cerebral dopamine neurotrophic factor/mesencephalic astrocyte-derived neurotrophic factor (CDNF/MANF), which regulates the Unfolded Protein Response (UPR). (F) Dopaminergic cell death leads to a lack of dopamine to oppose glutamate at synapses, causing excitotoxicity manifesting as loss of dendritic spine density; exercise can reduce excitotoxicity and restore dendritic spines. (G) Alpha-synuclein (α-Syn) binding toll-like receptor 2 (TLR2) on microglia and upregulation of toll-like receptor 4 (TLR4) causing activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome result in increased microglia activation and excessive pro-inflammatory cytokine release; exercise can increase anti-inflammatory cytokines to combat this, and can suppress the NLRP3 inflammasome. (H) Exercise increases aquaporin 4 (AQP4) receptors on astrocytic end-feet, which are downregulated in PD, and may augment glymphatic clearance by increasing arterial pulsatility, increasing clearance of proteins from the brain parenchyma.