Heba Ajmal

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder defined by the intracellular aggregation of α-synuclein and the loss of dopaminergic neurons.² The prodromal phase can last decades before motor symptoms manifest, offering a critical therapeutic window to intervene before irreversible neuronal loss occurs.^2,3 Standard diagnostics for prodromal markers like isolated REM sleep behavior disorder (iRBD) are expensive, inaccessible, or lack clinical specificity.^1,3 Consequently, there is an urgent need to establish scalable, blood-based screening biomarkers alongside innovative therapies.^3,4 Recent investigations highlight that intracellular α-synuclein accumulation overloads host clearance machinery, driving pathogenic protein export via extracellular vesicles (EVs) and exocytosis.^4,5 Delineating these cellular secretion mechanisms is vital for mapping an early diagnostic-to-therapeutic pipeline.^4,6

Objective: In this narrative review, we explored the parallel mechanisms by which neurons and astrocytes secrete pathogenic α-synuclein species due to lysosomal dysfunction, and evaluated how these pathways enable early serum EV diagnosis and glial-targeted therapeutic clearance.

Search Methods: An online search in the PubMed database was conducted from 2021 to 2026 using keywords including: “Parkinson’s disease”, “alpha-synuclein”, “extracellular vesicles”, “lysosomal exocytosis”, “astrocytes”, and “prodromal.”

Results: Studies indicate that intracellular degradation-resistant α-synuclein aggregates accumulate within the lysosomal lumen of primary neurons.⁵ When lysosomes suffer trafficking defects, cells resort to SNARE-dependent lysosomal exocytosis as a compensatory mechanism to export these toxic species.⁵ This pathway relies heavily on the vesicular SNARE protein VAMP7; expressing dominant-negative VAMP7 successfully suppresses neuronal secretion of pathogenic, seeding-competent α-synuclein aggregates by 80%.⁵ Parallelly, pathological α-synuclein overloads astrocytic lysosomes, downregulating cathepsin activity and altering LAMP1/LAMP2 levels.⁶ This astrocytic lysosomal failure forces a compensatory hypersecretion of glutamate transporter-1 (GLT-1)-positive astrocyte-derived extracellular vesicles (AEVs), spreading toxic pathology to neighboring healthy neurons.⁶

These exocrine pathways provide dual clinical diagnostic signals. Serum immunocapture of L1CAM-positive neuronally-derived extracellular vesicles (L1EVs) in a cohort of 576 participants accurately isolated elevated vesicular α-synuclein levels, identifying prodromal individuals with 90% diagnostic accuracy and predicting clinical phenoconversion with 80% accuracy.⁴ Complementarily, plasma assays show that GLT-1-positive AEV α-synuclein levels are uniquely elevated in PD patients compared to controls and multiple system atrophy (MSA) patients, providing reliable differentiation between distinct synucleinopathies.⁶

Therapeutically, capitalizing on astrocytic proteostasis offers a viable path to reverse this pathology. Co-culture models demonstrate that ventral midbrain (VM) astrocytes exert profound paracrine effects that rescue mitochondrial damage and completely arrest cell-to-cell aggregate propagation.⁷ Furthermore, in situ engineered astrocytes expressing a chimeric antigen receptor (CAR) fused with a truncated MerTK phagocytic receptor activate internal Rac1/Cdc42/RhoA signaling pathways.⁸ These CAR-astrocytes selectively eliminate toxic α-synuclein oligomers, suppress neuroinflammatory NF-κB signaling, protect dopaminergic tracks, and rescue motor and cognitive deficits in mice.⁸

Conclusions: Lysosomal dysfunction drives pathogenic α-synuclein release from both neurons and astrocytes.^4,5,6 Serum L1EV and plasma AEV biomarkers offer a highly accurate, non-invasive screening window to detect underlying synucleinopathy during its silent prodromal period.^4,6 Coupling these early screening tools with targeted VM-astrocyte or CAR-engineered glial therapies represents a powerful, dual-purpose clinical framework capable of clearing protein aggregates and stopping PD progression before irreversible motor disability occurs.^7,8

Works Cited:

1. Zhou Y, Liu X, Xu B. Research Progress on the Relationship between Parkinson’s Disease and REM Sleep Behavior Disorder. J Integr Neurosci. 2024;23(9):166. doi:10.31083/j.jin2309166
2. Stefani A, Antelmi E, Arnaldi D, et al. From mechanisms to future therapy: a synopsis of isolated REM sleep behavior disorder as early synuclein-related disease. Mol Neurodegener. 2025;20(19). doi:10.1186/s13024-025-00809-0
3. Neilson LE, Khattab YI, Lim MM. REM Sleep Behavior Disorder as a Prodromal Synucleinopathy: Updates on Clinical and Laboratory Biomarkers, and Implications for Neuroprotective Trials. Curr Neurol Neurosci Rep. 2025;25(1):73. doi:10.1007/s11910-025-01452-4
4. Yan S, Jiang C, Janzen A, et al. Neuronally Derived Extracellular Vesicle α-Synuclein as a Serum Biomarker for Individuals at Risk of Developing Parkinson Disease. JAMA Neurol. 2024;81(1):59-68. doi:10.1001/jamaneurol.2023.4398
5. Xie YX, Naseri NN, Fels J, et al. Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models. Nat Commun. 2022;13(1):4918. Published 2022 Aug 22. doi:10.1038/s41467-022-32625-1
6. Wang P, Lan G, Xu B, et al. α-Synuclein-carrying astrocytic extracellular vesicles in Parkinson pathogenesis and diagnosis. Transl Neurodegener. 2023;12(1):40. Published 2023 Aug 25. doi:10.1186/s40035-023-00372-y
7. Yang Y, Song JJ, Choi YR, et al. Therapeutic functions of astrocytes to treat α-synuclein pathology in Parkinson’s disease. Proc Natl Acad Sci U S A. 2022;119(29):e2110746119. doi:10.1073/pnas.2110746119
8. Du XY, Zhou J, Zhu J, et al. Attenuating α-synuclein pathology in mice with in situ engineered astrocytes. Transl Neurodegener. 2025;14(1):58. Published 2025 Nov 20. doi:10.1186/s40035-025-00518-0