Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions
Abstract α-Synucleinopathies constitute a spectrum of neurodegenerative disorders, including Parkinson’s disease (PD), Lewy body dementia (LBD), Multiple System Atrophy (MSA), and Alzheimer’s disease concurrent with LBD (AD-LBD). These disorders are unified by a pathological hallmark: aberrant misfo...
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| Format: | Article |
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BMC
2025-01-01
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| Series: | Molecular Neurodegeneration |
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| Online Access: | https://doi.org/10.1186/s13024-025-00797-1 |
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| author | Grace Kuo Ramhari Kumbhar William Blair Valina L. Dawson Ted M. Dawson Xiaobo Mao |
| author_facet | Grace Kuo Ramhari Kumbhar William Blair Valina L. Dawson Ted M. Dawson Xiaobo Mao |
| author_sort | Grace Kuo |
| collection | DOAJ |
| description | Abstract α-Synucleinopathies constitute a spectrum of neurodegenerative disorders, including Parkinson’s disease (PD), Lewy body dementia (LBD), Multiple System Atrophy (MSA), and Alzheimer’s disease concurrent with LBD (AD-LBD). These disorders are unified by a pathological hallmark: aberrant misfolding and accumulation of α-synuclein (α-syn). This review delves into the pivotal role of α-syn, the key agent in α-synucleinopathy pathophysiology, and provides a survey of potential therapeutics that target cell-to-cell spread of pathologic α-syn. Recognizing the intricate complexity and multifactorial etiology of α-synucleinopathy, the review illuminates the potential of various membrane receptors, proteins, intercellular spreading pathways, and pathological agents for therapeutic interventions. While significant progress has been made in understanding α-synucleinopathy, the pursuit of efficacious treatments remains challenging. Several strategies involving decreasing α-syn production and aggregation, increasing α-syn degradation, lowering extracellular α-syn, and inhibiting cellular uptake of α-syn are presented. The paper underscores the necessity of meticulous and comprehensive investigations to advance our knowledge of α-synucleinopathy pathology and ultimately develop innovative therapeutic strategies for α-synucleinopathies. Graphical Abstract |
| format | Article |
| id | doaj-art-260211aada2b4fdd8a67d0ee9a71db10 |
| institution | Kabale University |
| issn | 1750-1326 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj-art-260211aada2b4fdd8a67d0ee9a71db102025-01-26T12:52:27ZengBMCMolecular Neurodegeneration1750-13262025-01-0120112310.1186/s13024-025-00797-1Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventionsGrace Kuo0Ramhari Kumbhar1William Blair2Valina L. Dawson3Ted M. Dawson4Xiaobo Mao5Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of MedicineAbstract α-Synucleinopathies constitute a spectrum of neurodegenerative disorders, including Parkinson’s disease (PD), Lewy body dementia (LBD), Multiple System Atrophy (MSA), and Alzheimer’s disease concurrent with LBD (AD-LBD). These disorders are unified by a pathological hallmark: aberrant misfolding and accumulation of α-synuclein (α-syn). This review delves into the pivotal role of α-syn, the key agent in α-synucleinopathy pathophysiology, and provides a survey of potential therapeutics that target cell-to-cell spread of pathologic α-syn. Recognizing the intricate complexity and multifactorial etiology of α-synucleinopathy, the review illuminates the potential of various membrane receptors, proteins, intercellular spreading pathways, and pathological agents for therapeutic interventions. While significant progress has been made in understanding α-synucleinopathy, the pursuit of efficacious treatments remains challenging. Several strategies involving decreasing α-syn production and aggregation, increasing α-syn degradation, lowering extracellular α-syn, and inhibiting cellular uptake of α-syn are presented. The paper underscores the necessity of meticulous and comprehensive investigations to advance our knowledge of α-synucleinopathy pathology and ultimately develop innovative therapeutic strategies for α-synucleinopathies. Graphical Abstracthttps://doi.org/10.1186/s13024-025-00797-1Prion-likeα-synucleinSpreadingReceptorTherapeutic targets |
| spellingShingle | Grace Kuo Ramhari Kumbhar William Blair Valina L. Dawson Ted M. Dawson Xiaobo Mao Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions Molecular Neurodegeneration Prion-like α-synuclein Spreading Receptor Therapeutic targets |
| title | Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions |
| title_full | Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions |
| title_fullStr | Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions |
| title_full_unstemmed | Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions |
| title_short | Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions |
| title_sort | emerging targets of α synuclein spreading in α synucleinopathies a review of mechanistic pathways and interventions |
| topic | Prion-like α-synuclein Spreading Receptor Therapeutic targets |
| url | https://doi.org/10.1186/s13024-025-00797-1 |
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