Publication date: Oct 09, 2024
Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) are neurodegenerative disorders characterized by the accumulation of α-synuclein aggregates. α-synuclein forms droplets via liquid-liquid phase separation (LLPS), followed by liquid-solid phase separation (LSPS) to form amyloids, how this process is physiologically-regulated remains unclear. β-synuclein colocalizes with α-synuclein in presynaptic terminals. Here, we report that β-synuclein partitions into α-synuclein condensates promotes the LLPS, and slows down LSPS of α-synuclein, while disease-associated β-synuclein mutations lose these capacities. Exogenous β-synuclein improves the movement defects and prolongs the lifespan of an α-synuclein-expressing NL5901 Caenorhabditis elegans strain, while disease-associated β-synuclein mutants aggravate the symptoms. Decapeptides targeted at the α-/β-synuclein interaction sites are rationally designed, which suppress the LSPS of α-synuclein, rescue the movement defects, and prolong the lifespan of C. elegans NL5901. Together, we unveil a Yin-Yang balance between α- and β-synuclein underlying the normal and disease states of PD and DLB with therapeutical potentials.
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Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | Parkinson’s disease |
| disease | MESH | Dementia |
| disease | MESH | neurodegenerative disorders |
| disease | MESH | defects |
| drug | DRUGBANK | Isoxaflutole |
| pathway | REACTOME | Chromatin organization |
| pathway | REACTOME | Neurodegenerative Diseases |
| disease | MESH | death |
| disease | MESH | Zoonotic Infectious Diseases |
| pathway | REACTOME | Metabolism |
| drug | DRUGBANK | Polyethylene glycol |
| drug | DRUGBANK | Acetylcysteine |
| drug | DRUGBANK | Lysozyme |
| drug | DRUGBANK | Heparin |
| drug | DRUGBANK | Tretamine |
| disease | MESH | point mutations |
| drug | DRUGBANK | Dacarbazine |
| disease | MESH | Lewy Body Disease |
| pathway | KEGG | Parkinson disease |