| First Author | Wu Q | Year | 2019 |
| Journal | J Neurosci | Volume | 39 |
| Issue | 26 | Pages | 5080-5094 |
| PubMed ID | 31036761 | Mgi Jnum | J:276712 |
| Mgi Id | MGI:6316107 | Doi | 10.1523/JNEUROSCI.0060-19.2019 |
| Citation | Wu Q, et al. (2019) alpha-Synuclein (alphaSyn) Preformed Fibrils Induce Endogenous alphaSyn Aggregation, Compromise Synaptic Activity and Enhance Synapse Loss in Cultured Excitatory Hippocampal Neurons. J Neurosci 39(26):5080-5094 |
| abstractText | Synucleinopathies are characterized by the accumulation of insoluble alpha-synuclein (alphaSyn). To test whether alphaSyn aggregates modulate synaptic activity, we used a recently developed model in primary neurons for inducing alphaSyn pathology. We demonstrated that preformed fibrils (PFFs) generated with recombinant human alphaSyn compromised synaptic activity in a time- and dose-dependent manner and that the magnitude of these deficits correlated with the formation of alphaSyn pathology in cultured excitatory hippocampal neurons from both sexes of mice. Remarkably, acute passive infusion of alphaSyn PFFs from whole-cell patch-clamp pipette decreased mEPSC frequency within 10 min followed by induction of alphaSyn pathology within 1 d. Moreover, by direct addition of alphaSyn PFFs into culture medium, the formation of misfolded alphaSyn inclusions dramatically compromised the colocalization of synaptic markers and altered dynamic changes of dendritic spines, but the viability of neurons was not affected up to 7 d post-treatment with alphaSyn PFFs. Our data indicate that intraneuronal alphaSyn fibrils impaired the initiation of synaptogenesis and their physiological functions, thereby suggesting that targeting synaptic dysfunction in synucleinopathies may provide a promising therapeutic direction.SIGNIFICANCE STATEMENT Under pathological conditions, the presynaptic protein alpha-synuclein (alphaSyn) aggregates to form intraneuronal inclusions. To understand how and to what extent alphaSyn aggregates modulate synaptic activity before neuron loss, we demonstrate that alphaSyn preformed fibrils (PFFs) reduced synaptic activity in a dose- and time-dependent manner. The magnitude of these deficits correlated with the deposition of alphaSyn pathology, which dramatically compromised the colocalization of synaptic markers and altered the dendritic spine dynamics. The present work further highlights the impact of alphaSyn PFFs on synaptogenesis and physiological function, which may be applicable to other types of synucleinopathies. |
