Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration

Neurobiology of Disease

Fredric P. Manfredsson¹  Nicole K. Polinski²  Emily Schulz²  Christopher J. Kemp²  Timothy J. Collier²  Kelvin C. Luk²  Sheila Fleming²  Nicholas M. Kanaan³  Stephanie Celano⁴  Jack W. Lipton⁴  Virginia M. Lee⁴  Katrina L. Paumier⁴  Kathy Steece-Collier⁴  Elliott Dirr⁴  John Q. Trojanowski⁴  Caryl E. Sortwell⁴  Ivette M. Sandoval⁴ 

[1] Corresponding author at: Michigan State University, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA.;Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA;Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA;Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA;

关键词: Pre-formed fibrils;    Alpha-synuclein;    Propagation;    Neurodegeneration;    Rats;    Parkinson's disease;   

DOI  :  

来源: DOAJ

【 摘 要 】

Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (α-syn) into mice induce Parkinson's disease (PD)-like Lewy body (LB) pathology formed by aggregated α-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse α-syn pre-formed fibrils (PFF) injected into the striatum of rats would result in accumulation of LB-like intracellular inclusions and nigrostriatal degeneration. Sprague–Dawley rats received unilateral intrastriatal injections of either non-fibrillized recombinant α-syn or PFF mouse α-syn in 1- or 2- sites and were euthanized at 30, 60 or 180 days post-injection (pi). Both non-fibrillized recombinant α-syn and PFF α-syn injections resulted in phosphorylated α-syn intraneuronal accumulations (i.e., diffuse Lewy neurite (LN)- and LB-like inclusions) with significantly greater accumulations following PFF injection. LB-like inclusions were observed in several areas that innervate the striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars compacta (SNpc). α-Syn accumulations co-localized with ubiquitin, p62, and were thioflavin-S-positive and proteinase-k resistant, suggesting that PFF-induced pathology exhibits properties similar to human LBs. Although α-syn inclusions within the SNpc remained ipsilateral to striatal injection, we observed bilateral reductions in nigral dopamine neurons at the 180-day time-point in both the 1- and 2-site PFF injection paradigms. PFF injected rats exhibited bilateral reductions in striatal dopaminergic innervation at 60 and 180 days and bilateral decreases in homovanillic acid; however, dopamine reduction was observed only in the striatum ipsilateral to PFF injection. Although the level of dopamine asymmetry in PFF injected rats at 180 days was insufficient to elicit motor deficits in amphetamine-induced rotations or forelimb use in the cylinder task, significant disruption of ultrasonic vocalizations was observed. Taken together, our findings demonstrate that α-syn PFF are sufficient to seed the pathological conversion and propagation of endogenous α-syn to induce a progressive, neurodegenerative model of α-synucleinopathy in rats.

【 授权许可】

Unknown