α-突触核蛋白病谱系：从帕金森病到多系统萎缩的分子机制与靶向治疗进展

doi:10.3969/j.issn.1674-8115.2026.10.002

摘要/Abstract

摘要：

α-突触核蛋白病是一组以α-突触核蛋白（α-synuclein，α-syn）异常聚集为共同病理特征的神经退行性疾病，其疾病谱系涵盖帕金森病（Parkinson's disease，PD）、多系统萎缩（multiple system atrophy，MSA）等亚型。上述亚型在临床表现、病理分布和病程进展方面存在显著异质性。既往研究表明，PD以神经元内路易小体（Lewy bodies，LBs）为特征，病灶内α-syn呈对称双层β-折叠构象，其聚集传播受丝氨酸129位点（serine 129，Ser129）磷酸化驱动；MSA则以少突胶质细胞内的胶质胞浆包涵体（glial cytoplasmic inclusions，GCIs）为标志，病灶内α-syn形成特异性“希腊钥匙（Greek key）”拓扑结构，该α-syn聚集体的传播过程与微管聚合促进蛋白（tubulin polymerization-promoting protein，TPPP，又称p25α）密切相关。然而，PD与MSA在α-syn构象形成、聚集传播以及治疗靶点上的差异尚未得到系统整合，构象株系分型在精准治疗中的关键作用亦有待进一步阐明。基于此，该文通过系统梳理PD与MSA在分子病理学特征、聚集与传播机制、疾病特异性构象体系形成机制及靶向治疗策略等方面的差异，探讨构象株系分型与疾病表型及治疗策略分化之间的关系，对α-突触核蛋白病谱系的分子异质性与精准治疗进展进行综述，以期为基于病理特征的精准治疗研发提供理论依据。

关键词: α-突触核蛋白病, 帕金森病, 多系统萎缩, 蛋白构象株系, 微管聚合促进蛋白, 靶向治疗

Abstract:

α-Synucleinopathies are a group of neurodegenerative diseases characterized by the abnormal aggregation of α-synuclein (α-syn) as a common pathological feature. The disease spectrum includes Parkinson's disease (PD), multiple system atrophy (MSA), and other subtypes. These subtypes exhibit marked heterogeneity in clinical manifestations, pathological distribution, and disease progression. Previous studies have shown that PD is characterized by intraneuronal Lewy bodies (LBs), in which α-syn adopts a symmetric bilayer β-sheet conformation, and its aggregation and propagation are driven by phosphorylation at serine 129 (Ser129). In contrast, MSA is marked by glial cytoplasmic inclusions (GCIs) in oligodendrocytes, with α-syn in the lesions forming a unique "Greek key" topology, and the propagation of these α-syn aggregates is closely associated with tubulin polymerization-promoting protein (TPPP, also known as p25α). However, the differences between PD and MSA in α-syn conformational formation, aggregation and propagation, and therapeutic targets have not been systematically integrated, and the critical role of conformational strain typing in precision therapy remains to be further elucidated. Based on this, this review systematically compares the differences between PD and MSA in molecular pathological features, aggregation and propagation mechanisms, disease-specific conformational strain formation mechanisms, and targeted therapeutic strategies. It also explores the relationship between conformational strain classification and the divergence of disease phenotypes and therapeutic strategies, and reviews advances in understanding the molecular heterogeneity of the α-synucleinopathy spectrum and developing precision therapies, aiming to provide a theoretical basis for the research and development of precision therapies based on pathological features.

Key words: α-synucleinopathy, Parkinson's disease (PD), multiple system atrophy (MSA), protein conformational strain, tubulin polymerization-promoting protein (TPPP), targeted therapy

中图分类号:

R741

张凤娟, 李彬寅, 李洪涛. α-突触核蛋白病谱系：从帕金森病到多系统萎缩的分子机制与靶向治疗进展[J]. 上海交通大学学报（医学版）, 2026, 46(10): 1323-1330.

Zhang Fengjuan, Li Binyin, Li Hongtao. Spectrum of α-synucleinopathies: molecular mechanisms and advances in targeted therapy from Parkinson' s disease to multiple system atrophy[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026,(10): 1323-1330.

图/表 2

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Pathological feature	PD	MSA
Main affected cells	Neurons (especially nigral dopaminergic neurons)^[20]	Oligodendrocytes^[19]
Pathological inclusions	LBs^[11]	GCIs^[21]
α-syn fibril structure	Symmetric double-layered β-sheet (Lewy fold, with no specific topology)^[20]	"Greek key" topology^[4]
Key modification/interaction	Ser129 phosphorylation promotes aggregation^[18]	TPPP binding to α-syn accelerates aggregation ^[4]
Cellular impact	Oxidative stress and Ca²⁺ dysregulation in neurons^[20]	Abnormal lipid rafts, acidic pH, and metal ion concentrations in oligodendrocytes^[19]
Cell-specific mechanism	Impaired synaptic vesicle trafficking; dopamine-related metabolic toxicity^[17]	Impaired myelin synthesis; abnormal oligodendrocyte-neuron interaction^[19]
Propagation route	Synaptic proximity transmission^[17]; secretion into body fluids via nonclassical pathways^[20]	Exosomal/paracrine secretion; cytosolic transfer; autocrine/endocytic uptake^[12]
Pathological spread	From the brainstem (cholinergic regions) to the cortex and limbic system^[20]	Extensive white matter involvement; rapid spread^[13]
Functional impact	Dopaminergic neuronal loss→motor dysfunction^[20]	Myelin destruction→autonomic dysfunction+motor dysfunction^[19]
Therapeutic target	Inhibit α-syn oligomerization (e.g., Ser129 inhibitors); enhance autophagy^[22]	Block TPPP-α-syn interaction; modulate the pathological microenvironment of oligodendrocytes^[4]

Pathological feature	PD	MSA
Main affected cells	Neurons (especially nigral dopaminergic neurons)^[20]	Oligodendrocytes^[19]
Pathological inclusions	LBs^[11]	GCIs^[21]
α-syn fibril structure	Symmetric double-layered β-sheet (Lewy fold, with no specific topology)^[20]	"Greek key" topology^[4]
Key modification/interaction	Ser129 phosphorylation promotes aggregation^[18]	TPPP binding to α-syn accelerates aggregation ^[4]
Cellular impact	Oxidative stress and Ca²⁺ dysregulation in neurons^[20]	Abnormal lipid rafts, acidic pH, and metal ion concentrations in oligodendrocytes^[19]
Cell-specific mechanism	Impaired synaptic vesicle trafficking; dopamine-related metabolic toxicity^[17]	Impaired myelin synthesis; abnormal oligodendrocyte-neuron interaction^[19]
Propagation route	Synaptic proximity transmission^[17]; secretion into body fluids via nonclassical pathways^[20]	Exosomal/paracrine secretion; cytosolic transfer; autocrine/endocytic uptake^[12]
Pathological spread	From the brainstem (cholinergic regions) to the cortex and limbic system^[20]	Extensive white matter involvement; rapid spread^[13]
Functional impact	Dopaminergic neuronal loss→motor dysfunction^[20]	Myelin destruction→autonomic dysfunction+motor dysfunction^[19]
Therapeutic target	Inhibit α-syn oligomerization (e.g., Ser129 inhibitors); enhance autophagy^[22]	Block TPPP-α-syn interaction; modulate the pathological microenvironment of oligodendrocytes^[4]

Therapeutic dimension	PD	MSA
Core pathological mechanism	Intraneuronal α-syn aggregation; Ser129 phosphorylation-driven aggregation^[18]	Oligodendroglial α-syn aggregation; TPPP interaction-mediated acceleration of aggregation^[14]
Targeting α-syn	1. Inhibit aggregation: small-molecule inhibitors (curcumin derivatives, EGCG) ; conformation-specific antibodies (Prasinezumab) 2. Enhance clearance: lysosomal activation; ASO-mediated SNCA silencing 3. Block propagation: passive immunization (PRX002) 4. Immune clearance: PD-specific anti-α-syn fibril antibodies^[20]	1. Target TPPP: block the TPPP-α-syn interaction (e.g., TPPP inhibitors) 2. Inhibit oligodendroglial α-syn aggregation; modulate the acidic microenvironment and metal ion balance 3. Immune clearance: MSA-specific anti-α-syn fibril antibodies^[21]
Targeting genetic mutations	LRRK2 mutations: LRRK2 inhibitors (e.g., GNE-0877/DNL201)^[29]; GBA1 mutations: GCase chaperone (afegostat tartrate, AT2101)^[30]	COQ2 mutations: coenzyme Q10 supplementation^[31]
Neuroprotection and anti-inflammation	GLP-1R agonists (e.g., NN9055)^[32]; anti-inflammatory strategies: reduction of microglial activation^[20]	Anti-inflammatory strategies: reduction of microglial activation^[33]; iron chelation therapy^[34]
Symptomatic treatment	Dopaminergic replacement (levodopa, DA agonists); non-motor symptoms: cholinesterase inhibitors (cognitive symptoms), SSRIs (depression)^[17]	Orthostatic hypotension: midodrine, droxidopa; urinary dysfunction: mirabegron for overactive bladder^[14]
Representative clinical trials	αSyn-ScFv (Prasinezumab, Phase Ⅱ, NCT03100149)^[35]; ASO gene therapy (BIIB094, Phase Ⅰ, NCT04165486)^[36]	S1P5 receptor agonist (ONO-2808, Phase Ⅱ)^[37]; stem cell therapy (mesenchymal stem cells, Phase Ⅰ/Ⅱ, NCT05107711)^[13]
Challenges and future directions	Disease heterogeneity complicates treatment efficacy; disease-specific therapies are needed; early diagnosis and biomarkers are important^[38]	Poor blood-brain barrier penetration; difficulties in early diagnosis; narrow therapeutic window^[21]

Therapeutic dimension	PD	MSA
Core pathological mechanism	Intraneuronal α-syn aggregation; Ser129 phosphorylation-driven aggregation^[18]	Oligodendroglial α-syn aggregation; TPPP interaction-mediated acceleration of aggregation^[14]
Targeting α-syn	1. Inhibit aggregation: small-molecule inhibitors (curcumin derivatives, EGCG) ; conformation-specific antibodies (Prasinezumab) 2. Enhance clearance: lysosomal activation; ASO-mediated SNCA silencing 3. Block propagation: passive immunization (PRX002) 4. Immune clearance: PD-specific anti-α-syn fibril antibodies^[20]	1. Target TPPP: block the TPPP-α-syn interaction (e.g., TPPP inhibitors) 2. Inhibit oligodendroglial α-syn aggregation; modulate the acidic microenvironment and metal ion balance 3. Immune clearance: MSA-specific anti-α-syn fibril antibodies^[21]
Targeting genetic mutations	LRRK2 mutations: LRRK2 inhibitors (e.g., GNE-0877/DNL201)^[29]; GBA1 mutations: GCase chaperone (afegostat tartrate, AT2101)^[30]	COQ2 mutations: coenzyme Q10 supplementation^[31]
Neuroprotection and anti-inflammation	GLP-1R agonists (e.g., NN9055)^[32]; anti-inflammatory strategies: reduction of microglial activation^[20]	Anti-inflammatory strategies: reduction of microglial activation^[33]; iron chelation therapy^[34]
Symptomatic treatment	Dopaminergic replacement (levodopa, DA agonists); non-motor symptoms: cholinesterase inhibitors (cognitive symptoms), SSRIs (depression)^[17]	Orthostatic hypotension: midodrine, droxidopa; urinary dysfunction: mirabegron for overactive bladder^[14]
Representative clinical trials	αSyn-ScFv (Prasinezumab, Phase Ⅱ, NCT03100149)^[35]; ASO gene therapy (BIIB094, Phase Ⅰ, NCT04165486)^[36]	S1P5 receptor agonist (ONO-2808, Phase Ⅱ)^[37]; stem cell therapy (mesenchymal stem cells, Phase Ⅰ/Ⅱ, NCT05107711)^[13]
Challenges and future directions	Disease heterogeneity complicates treatment efficacy; disease-specific therapies are needed; early diagnosis and biomarkers are important^[38]	Poor blood-brain barrier penetration; difficulties in early diagnosis; narrow therapeutic window^[21]