| First Author | Szegő ÉM | Year | 2021 |
| Journal | Front Neurosci | Volume | 15 |
| Pages | 696440 | PubMed ID | 34326719 |
| Mgi Jnum | J:343002 | Mgi Id | MGI:6730627 |
| Doi | 10.3389/fnins.2021.696440 | Citation | Szego EM, et al. (2021) A beta-Wrapin Targeting the N-Terminus of alpha-Synuclein Monomers Reduces Fibril-Induced Aggregation in Neurons. Front Neurosci 15:696440 |
| abstractText | Reducing alpha-synuclein pathology constitutes a plausible strategy against Parkinson's disease. As we recently demonstrated, the beta-wrapin protein AS69 binds an N-terminal region in monomeric alpha-synuclein, interferes with fibril nucleation, and reduces alpha-synuclein aggregation in vitro and in a fruit fly model of alpha-synuclein toxicity. The aim of this study was to investigate whether AS69 also reduces alpha-synuclein pathology in mammalian neurons. To induce alpha-synuclein pathology, primary mouse neurons were exposed to pre-formed fibrils (PFF) of human alpha-synuclein. PFF were also injected into the striatum of A30P-alpha-synuclein transgenic mice. The extent of alpha-synuclein pathology was determined by phospho-alpha-synuclein staining and by Triton X-100 solubility. The degeneration of neuronal somata, dendrites, and axon terminals was determined by immunohistochemistry. AS69 and PFF were taken up by primary neurons. AS69 did not alter PFF uptake, but AS69 did reduce PFF-induced alpha-synuclein pathology. PFF injection into mouse striatum led to alpha-synuclein pathology and dystrophic neurites. Co-injection of AS69 abrogated PFF-induced pathology. AS69 also reduced the PFF-induced degeneration of dopaminergic axon terminals in the striatum and the degeneration of dopaminergic dendrites in the substantia nigra pars reticulata. AS69 reduced the activation of astroglia but not microglia in response to PFF injection. Collectively, AS69 reduced PFF-induced alpha-synuclein pathology and the associated neurodegeneration in primary neurons and in mouse brain. Our data therefore suggest that small proteins binding the N-terminus of alpha-synuclein monomers are promising strategies to modify disease progression in Parkinson's disease. |
