Neurodegeneration and Neuroinflammation are Linked, but Independent of α-Synuclein Inclusions, in a Seeding/Spreading Mouse Model of Parkinson’s Disease

Abstract

<jats:title>Abstract</jats:title> <jats:p><jats:bold>Background</jats:bold>: Akey process of neurodegeneration in Parkinson’s disease (PD) is the transneuronal spreading of a-synuclein. Alpha-synuclein is a presynaptic protein that is implicated in the pathogenesis of PD and other synucleinopathies, where it forms, upon intracellular aggregation, pathological inclusions.Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarilytransneuronal spreading of a-synuclein particles,inclusion formation, or other mechanisms, such as inflammation,that cause neurodegeneration in PDis unclear.<jats:bold>Methods</jats:bold>: We used spreading/aggregation ofa-synuclein induced by intracerebral injection of a-synucleinpreformed fibrils into the mouse brain to address this question. We performed quantitative histological analysis for a-synuclein inclusions, neurodegeneration, and microgliosis in different brain regions, and a gene expression profiling of the ventral midbrain, at two different timepoints after disease induction.<jats:bold>Results</jats:bold>: We observed significant neurodegeneration and microgliosis in brain regions not only with,but alsowithouta-synuclein inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. In longitudinal gene expression profiling experiments, we observedearly and unique alterationslinkedto microglial mediated inflammation that preceded neurodegeneration, indicating an active role of microglia in inducing neurodegeneration. Our observations indicate that a-synuclein inclusion formation is not the major driverin the early phases of PD-like neurodegeneration, but that diffusible, oligomeric a-synuclein species,which induce unusual microglial reactivity, play a key role in this process.<jats:bold>Conclusion</jats:bold>: Our findings uncover new features of a-synuclein induced pathologies, in particular microgliosis, and point to the necessity of a broader view of the process of “prion-like spreading” of that protein.</jats:p>

Animal models of Parkinson’s disease: a guide to selecting the optimal model for your research

“…Accordingly, mitochondrial fragmentation and dysfunction are observed in rats injected with AAV overexpressing A53T human -synuclein [109] and in mice injected in the striatum with α-synuclein PPFs [110,111]. Reduced mitochondrial function and degeneration of mtDNA was similarly seen in SNCA A53T transgenic mice [112].…”

Meta-analysis for Discovering Which Genes are Differentially Expressed in Neuroinflammation

“…Study D [4] entails the transneuronal coverage of alpha-synuclein in PD. Alpha-synuclein aggregation encouraged by the injection of alpha-synuclein preformed fibrils into mouse cerebrum was utilized.…”