Neurodegeneration and neuroinflammation are linked, but independent of alpha-synuclein inclusions, in a seeding/spreading mouse model of Parkinson's disease

Pierre Garcia, Wiebke Jürgens-Wemheuer, Oihane Uriarte Huarte, Alessandro Michelucci, Annette Masuch, Simone Brioschi, Andreas Weihofen, Eric Koncina, Djalil Coowar, Tony Heurtaux, Enrico Glaab, Rudi Balling, Carole Sousa, Tony Kaoma, Nathalie Nicot, Tatjana Pfander, Walter Schulz-Schaeffer, Ahmad Allouche, Nicolas Fischer, Knut BiberFelix Kleine-Borgmann, Michel Mittelbronn, Marek Ostaszewski, Kristopher J. Schmit, Manuel Buttini*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

A key pathological process in Parkinson's disease (PD) is the transneuronal spreading of α-synuclein. Alpha-synuclein (α-syn) is a presynaptic protein that, in PD, forms pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of α-syn particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used a model of spreading of α-syn induced by striatal injection of α-syn preformed fibrils into the mouse striatum to address this question. We performed quantitative analysis for α-syn inclusions, neurodegeneration, and microgliosis in different brain regions, and generated gene expression profiles of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also without α-syn inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. Using longitudinal gene expression profiling, we observed early gene expression changes, linked to neuroinflammation, that preceded neurodegeneration, indicating an active role of microglia in this process. Altered gene pathways overlapped with those typical of PD. Our observations indicate that α-syn inclusion formation is not the major driver in the early phases of PD-like neurodegeneration, but that microglia, activated by diffusible, oligomeric α-syn, may play a key role in this process. Our findings uncover new features of α-syn induced pathologies, in particular microgliosis, and point to the necessity for a broader view of the process of α-syn spreading.

Original languageEnglish
Pages (from-to)935-960
Number of pages26
JournalGLIA
Volume70
Issue number5
Early online date29 Jan 2022
DOIs
Publication statusPublished - May 2022

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