α-Synuclein fibril-induced paradoxical structural and functional defects in hippocampal neurons

Acta Neuropathologica Communications

Jose Carlos Gonzalez¹  John W. Mclean¹  Jada H. Vaden¹  Gokulakrishna Banumurthy¹  Linda Overstreet-Wadiche¹  Jessica M. Froula²  Benjamin W. Henderson²  Jeremy H. Herskowitz²  Laura A. Volpicelli-Daley²  Yumei Wu³ 

[1] Department of Neurobiology, University of Alabama at Birmingham;Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham;Department of Neuroscience, Yale University School of Medicine;

关键词: α-Synuclein;    Lewy body;    Lewy neurite;    Dendritic spines;    Fibril;    Parkinson’s disease;   

DOI  :  10.1186/s40478-018-0537-x

来源: DOAJ

【 摘 要 】

Abstract Neuronal inclusions composed of α-synuclein (α-syn) characterize Parkinson’s Disease (PD) and Dementia with Lewy bodies (DLB). Cognitive dysfunction defines DLB, and up to 80% of PD patients develop dementia. α-Syn inclusions are abundant in the hippocampus, yet functional consequences are unclear. To determine if pathologic α-syn causes neuronal defects, we induced endogenous α-syn to form inclusions resembling those found in diseased brains by treating hippocampal neurons with α-syn fibrils. At seven days after adding fibrils, α-syn inclusions are abundant in axons, but there is no cell death at this time point, allowing us to assess for potential alterations in neuronal function that are not caused by neuron death. We found that exposure of neurons to fibrils caused a significant reduction in mushroom spine densities, adding to the growing body of literature showing that altered spine morphology is a major pathologic phenotype in synucleinopathies. The reduction in spine densities occurred only in wild type neurons and not in neurons from α-syn knockout mice, suggesting that the changes in spine morphology result from fibril-induced corruption of endogenously expressed α-syn. Paradoxically, reduced postsynaptic spine density was accompanied by increased frequency of miniature excitatory postsynaptic currents (EPSCs) and presynaptic docked vesicles, suggesting enhanced presynaptic function. Action-potential dependent activity was unchanged, suggesting compensatory mechanisms responding to synaptic defects. Although activity at the level of the synapse was unchanged, neurons exposed to α-syn fibrils, showed reduced frequency and amplitudes of spontaneous Ca2+ transients. These findings open areas of research to determine the mechanisms that alter neuronal function in brain regions critical for cognition at time points before neuron death.

【 授权许可】

Unknown