BACKGROUND: Clarifying the interactions between multiple signaling pathways and axonal pathological alterations, and elucidating the role and mechanisms of axonal degeneration in the onset and progression of Parkinson’s disease will pave the way for research on the pathogenesis and pathological mechanisms of Parkinson’s disease centered around axonal degenerative changes.
OBJECTIVE: Through in-depth analysis of the roles and interactions of the signaling pathways mentioned in this review during the occurrence and development of Parkinson’s disease, to uncover potential clinical early warning mechanisms and explore novel strategies for prevention and treatment, including targeted gene sites, drug therapy, and rehabilitation interventions.
METHODS: A search of the PubMed database was conducted using the following keywords: “Parkinson, PD, axonal regeneration, aging, α-syn, pathological mechanism, autopsy, mitochondria, ER stress, inflammatory response, Nrf2/ Keap1, BDNF, NGF, NT3/TrkC, GDNF, RhoA, Rac/Cdc42, Wnt/β-catenin, SHH, Notch, Slit-Robo, Ephrin, Netrin, Semaphorin, integrin, ubiquitin-proteasome, autophagy-lysosome, apoptosis, exercise.” Another search of CNKI database was conducted using the search terms of “Parkinson’s, axonal degeneration, exercise, oxidative stress, brain-derived neurotrophic factor.” Literature was screened based on inclusion and exclusion criteria, and 101 articles were finally included for review and analysis.
RESULTS AND CONCLUSION: Studies have shown that Parkinson’s disease lesions initially occur in the limbic system region of the brain or the olfactory bulb, and that early axonal degeneration usually precedes cytosolic degeneration. Abnormal protein folding and aggregation, mitochondrial dysfunction, endoplasmic reticulum stress, and inflammatory responses are among the signaling pathways that may directly lead to axonal damage. At the same time, signaling pathways involved in cellular stress responses, neurotrophic factors, cytoskeletal regulation, development and regeneration, axonal growth and guidance, and removal of abnormal proteins contribute to the repair of damaged axons. Therefore, the prevention and treatment strategies for Parkinson’s disease, should focus on promoting the activation and expression of repair pathways. For instance, the use of quinacrine and clorgiline or the activation of brain-derived neurotrophic factor expression through exercise may effectively facilitate axonal repair. Additionally, inhibiting the aberrant activation of damage-related pathways is a crucial aspect of treatment strategies. Such approaches include gene knockout of α-synuclein, Parkin, or the use of drugs like empagliflozin to reduce oxidative stress and inflammation, potentially delaying the progression of Parkinson’s disease.