Key Takeaways & Executive Findings
- •• Early axonal degeneration precedes cell body degeneration in Parkinson's disease, with initial lesions in the limbic system or olfactory bulb. • Multiple signaling pathways contribute to axonal damage, including abnormal protein aggregation, mitochondrial dysfunction, ER stress, and inflammation. • Repair pathways such as neurotrophic factors, cytoskeletal regulation, and axonal guidance can be activated to promote axonal repair. • Combining inhibition of damage pathways and activation of repair pathways (e.g., via drugs or exercise) may offer novel therapeutic strategies.
Abstract
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 may directly lead to axonal damage; meanwhile, cellular stress responses, neurotrophic factors, cytoskeletal regulation, development and regeneration, axonal growth and guidance, and clearance of abnormal proteins contribute to the repair of damaged axons. Therefore, prevention and treatment strategies for Parkinson's disease should focus on promoting the activation and expression of repair pathways, such as the use of quinacrine and niclosamide or exercise-induced activation of brain-derived neurotrophic factor and other axonal repair pathways, which can effectively promote axonal repair; at the same time, inhibiting abnormal activation of damage pathways is also a key strategy, including knocking out α-synuclein, Parkin genes or using drugs such as empagliflozin to reduce oxidative stress and inflammatory responses, potentially delaying the progression of Parkinson's disease.
1. Introduction
Parkinson's disease is the second most common neurodegenerative disease, affecting 1%-2% of people over 65 years old. With the increase in global average population age and life expectancy, the incidence of Parkinson's disease is expected to double by 2030 [1]. As a neurodegenerative disease, the main pathological hallmarks of Parkinson's disease are progressive degeneration of dopaminergic neurons in the substantia nigra and typical α-synuclein aggregation, leading to a series of motor and non-motor symptoms [2]. The former mainly includes tremor, rigidity, bradykinesia, and postural and gait abnormalities, while non-motor symptoms are mainly reflected in olfactory loss or impairment, rapid eye movement sleep behavior disorder, depression, anxiety, cardiac sympathetic denervation, and constipation [3]. Non-motor symptoms often appear before motor symptoms [4]. Studies have shown that the lesions of Parkinson's disease initially occur in the limbic system region of the brain or the olfactory bulb, and early axonal degeneration usually precedes cell body degeneration [5]. Clarifying the interactions between multiple signaling pathways and axonal pathological changes, and exploring the role and mechanism of axonal degeneration in the occurrence and development of Parkinson's disease will be beneficial for research on the pathogenesis and pathological mechanisms of Parkinson's disease centered on axonal degeneration, and provide references for discovering new strategies for early warning and prevention of clinical Parkinson's disease. This article deeply analyzes the roles and interrelationships of the main signaling pathways of axonal damage and repair in the occurrence and development of Parkinson's disease, aiming to reveal potential clinical early warning mechanisms and explore new prevention and treatment strategies such as targeted gene sites, drug therapy, and rehabilitation interventions.
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WANG Jiao, SONG Wenjun, XIN Rui, LIU Wei, YING Zhenhao (2026). Signaling pathways associated with dopaminergic neuronal axonal degeneration in Parkinson's disease. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21350
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Frequently Asked Questions
What is the role of axonal degeneration in Parkinson's disease?
Axonal degeneration is an early event in Parkinson's disease, often preceding neuronal cell body degeneration. It contributes to the progressive loss of dopaminergic neurons and the onset of motor and non-motor symptoms.
Which signaling pathways are involved in axonal damage in Parkinson's disease?
Key pathways include abnormal protein aggregation (e.g., α-synuclein), mitochondrial dysfunction, endoplasmic reticulum stress, and inflammatory responses, which directly lead to axonal damage.
How can axonal repair be promoted in Parkinson's disease?
Activation of repair pathways such as neurotrophic factors (e.g., BDNF), cytoskeletal regulation, and axonal guidance signals can promote axonal repair. Strategies include exercise and certain drugs like quinacrine and niclosamide.
What are potential therapeutic strategies for Parkinson's disease based on this review?
Combining inhibition of damage pathways (e.g., reducing oxidative stress and inflammation) with activation of repair pathways (e.g., via exercise or drugs) may offer novel therapeutic approaches to delay disease progression.
What is the significance of early axonal degeneration in Parkinson's disease diagnosis?
Early axonal degeneration may serve as an early warning mechanism, as it occurs before cell body degeneration and may be detectable in the limbic system or olfactory bulb, potentially aiding in early diagnosis.
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