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Lookup NU author(s): Professor David BrooksORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
Alpha-synuclein (a-syn) can aggregate and form toxic oligomers and insoluble fibrils which are the main component of Lewy bodies. Intra-neuronal Lewy bodies are a major pathological characteristic of Parkinson’s disease (PD). These fibrillar structures act as seeds and accelerate the aggregation of monomeric a-syn. Indeed, recent studies show that injection of preformed a-syn fibrils (PFF) into the rodent brain induces aggregation of the endogenous monomeric a-syn resulting in neuronal dysfunction and eventual cell death. We injected 8 µg of murine a-syn PFF, or soluble monomeric a-syn into the right striatum of rats. The animals were monitored behaviourally using the cylinder test, which measures paw asymmetry, and the corridor task that measures lateralized sensorimotor response to sugar treats. In vivo PET imaging was performed after 6, 13 and 22 weeks using [11C]DTBZ, a marker of the vesicular monoamine 2 transporter (VMAT2), and after 15 and 22 weeks using [11C]UCB-J, a marker of synaptic SV2A protein in nerve terminals . Histology was performed at the 3 time points using antibodies against dopaminergic markers, aggregated a-syn, and MHCII to evaluate the immune response. While the a-syn PFF injection caused only mild behavioural changes, [11C]DTBZ PET showed significant, and progressive decreased VMAT2 binding in the ipsilateral striatum. This was accompanied by a small progressive decrease in [11C]UCB-J binding in the same area. In addition, our histological analysis revealed a gradual spread of misfolded a-syn pathology in areas anatomically connected to striatum that became bilateral with time. The striatal a-syn PFF injection resulted in a progressive unilateral degeneration of dopamine terminals and an early and sustained presence of MHCII positive ramified microglia in the ipsilateral striatum and substantia nigra. Our study shows that striatal injections of a-syn fibrils induces progressive pathological synaptic dysfunction prior to cell death that can be detected in vivo with PET. We confirm intrastriatal injection of a-syn PFFs provides a model of progressive a-syn pathology with loss of dopaminergic and synaptic function accompanied by neuroinflammation, as found in human PD.
Author(s): Thomsena MB, Ferreira SA, Schachta AC, Jacobsena J, Simonsena M, Betzerb C, Jensen PH, Brooks DJ, Landau AM, Romero-Ramos M
Publication type: Article
Publication status: Published
Journal: Neurobiology of Disease
Print publication date: 01/02/2021
Online publication date: 24/12/2020
Acceptance date: 17/12/2020
Date deposited: 17/12/2020
ISSN (print): 0969-9961
ISSN (electronic): 1095-953X
Publisher: Academic Press
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