Longitudinal follow-up and characterization of a robust rat model for Parkinson's disease based on overexpression of alpha-synuclein with adeno-associated viral vectors

Abstract

This%is%the%accepted%author%manuscript%of%the%publication%% % % Longitudinal+follow.up+and+characterization+of+a+robust+rat+ model+for+Parkinson's+disease+based+on+overexpression+of+ alpha.synuclein+with+adeno.associated+viral+vectors.+ % % By%Van%der%Perren%A,%Toelen%J,%Casteels%C,%Macchi%F,%Van%Rompuy%AS,%Sarre%S,% Casadei%N,%Nuber%S,%Himmelreich%U,%Osorio%Garcia%MI,%Michotte%Y,%D'Hooge%R,% Bormans% G,% Van% Laere% K,% Gijsbers% R,% Van% den% Haute% C,% Debyser% Z,% Baekelandt%V.% % % Published%in%Neurobiol%Aging.%2015%Mar;36(3):1543[58.%% doi:%10.1016/j.neurobiolaging.2014.11.015.% % % Direct%link%to%the%final%version%of%the%article:% Abstract Testing of new therapeutic strategies for Parkinson's disease (PD) is currently hampered by the lack of relevant and reproducible animal models. Here, we developed a robust rat model for PD by injection of adeno-associated viral vectors (rAAV2/7) encoding -synuclein into the substantia nigra, resulting in reproducible nigrostriatal pathology and behavioral deficits in a 4 weeks time period. Progressive dopaminergic dysfunction was corroborated by histopathological and biochemical analysis, motor behavior testing and in vivo microdialysis. L-DOPA treatment was found to reverse the behavioral phenotype. Non-invasive PET imaging and MR spectroscopy allowed longitudinal monitoring of neurodegeneration. In addition, insoluble -synuclein aggregates were formed in this model. This -synuclein rat model shows improved face and predictive validity, and therefore offers the possibility toreliably test novel therapeutics. Furthermore, it will be of great value for further research into the molecular pathogenesis of PD and the importance of -synuclein aggregation in the disease process.

Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration

“…Acute overexpression of ␣-synuclein in SNpc neurons results in the accumulation of nitrosylated/oxidized ␣-synuclein in the soma of surviving dopaminergic neurons 4 weeks post-viral transduction (15,16,23). Analysis of serial brain sections for nitrosylated/oxidized ␣-synuclein demonstrated abundant abnormal ␣-synuclein in the soma of surviving THϩ neurons in both G2019Sϩ and G2019SϪ rats (Fig.…”

Microglial phenotypes in Parkinson’s disease and animal models of the disease

“…Although none of these models replicate the main hallmarks of PD, such as progressive and severe loss of DA neurons and motor deficits, they have greatly contributed to the understanding of α-synuclein-induced toxicity. Alternative models include mice overexpressing human wild type α-synuclein under the Thy-1 promoter (Chesselet et al, 2012) or the tyrosine hydroxylase promoter (Su et al, 2008), and viral vector driven α-synuclein overexpression in rodents (Decressac et al, 2012; Lo Bianco et al, 2002; Sanchez-Guajardo et al, 2010; Van der Perren et al, 2015; Yamada et al, 2004) and primates (Eslamboli et al, 2007). Viral vector-based models show a progressive degeneration of nigrostriatal neurons that is associated with gradual motor impairment (Decressac et al, 2012; Van der Perren et al, 2015).…”

α-Synuclein strains cause distinct synucleinopathies after local and systemic administration

“…Studies with inoculation of recombinant fibrils or pathogenic brain lysates in rodent brain triggered a-SYN pathology with varying efficiencies and moderate neuronal loss 11,12 . In contrast, recombinant adeno-associated viral vector-mediated (rAAV) overexpression of a-SYN in rodent and primate brain induces time-dependent robust behavioural impairment and dopaminergic neurodegeneration 13,14 . In this study, we compared the in vivo properties of a-SYN oligomers and two distinct a-SYN strains ('fibrils' and 'ribbons') (Extended Data Fig.…”