Spectrum of α-synucleinopathies: molecular mechanisms and advances in targeted therapy from Parkinson' s disease to multiple system atrophy

doi:10.3969/j.issn.1674-8115.2026.10.002

Abstract

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

CLC Number:

R741

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.

Figures/Tables 2

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References 53

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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]