Special LMNN SEMINAR // 2 talks, 20 min. each

1. "Inclusion-Independent Neurodegeneration in a Mouse Synuclein-Spreading Model of PD: an Active Role for Microglia?"
 
A key process in many types of chronic neurodegeneration is the transneuronal spreading of aggregation-prone proteins, such as a-synuclein. Alpha-synuclein is a presynaptic protein that is implicated in the pathogenesis of Parkinson’s disease (PD) and other synucleopathies, where it forms, upon intracellular aggregation, pathological inclusions. Notably, transneuronal spreading of a-synuclein pathology appears as a basic mechanism of PD progression. Whether transneuronal spreading of a-synuclein particles, aggregation formation, or other mechanisms are directly causing neurodegeneration is unclear. Here, we use a model of spreading/aggregation of a-synuclein induced by intracerebral injection of preformed fibrils into mouse brain to address this question. We observed significant neurodegeneration and microgliosis in brain regions with, but also, just as importantly as without, a-synuclein inclusions, and these regions were either close or distant from the fibril injection site. We also observed that the level of microgliosis in injured brain regions
was unusually strong, and didn’t correlate with neurodegeneration. In gene epxression profiling studies, we couldn’t detect any changes in the expression of usual proinflammatory cytokines and chemokines that a typically enhanced during neuroinflammation, but instead observed that modulations of factors such as Toll-like-rector 2, TREM2, NAPDH oxidase 2, and prostaglandin synthesis components indicated an unique microglial activation profile that could promote neurodegeneration in susceptible brain regions. Our observations indicate that inclusion formation may not be the only driver of PD-like neurodegeneration, but that other factors, such as diffusible a-synuclein species, or unique microglia activity, play a role in the process. Our findings uncover novel features of a-synuclein induced pathologies, and point to the necessity of a broader view of the process of “prion-like spreading” of that protein.  

 
"Early Gene Expression Changes in Dopaminergic Neurons Precede PD-Related Neurodegeneration in Synuclein-Based Mouse Models of PD: A Possible New Path to Biomarker Discovery"
 
Understanding early, and therefore often subtle, disease processes in Parkinson’s disease (PD) is essential for the identification of biomarkers and the development of disease modifying cures. But in patients, and in many PD animal models, measurable neurological symptoms occur only at disease stages in which neuronal injury and loss has typically already progressed beyond repair. To investigate if measures of gehn expression profile changes help detect early disease processes, and thus open the way to biomarker, we investigated those profiles in the brain of synuclein-based genetic and induced PD models. - We investigated gene expression profiles in brain extracts of these models, and compared them with behavioural and neuropathological measures. By analyzing the ventral midbrain at different ages, or time-points of disease progression, we drew out changes in gene expression patterns that coincided, and often preceded, with subtle, early motor disturbances, and were, for the most part, independent of neuropathological changes such as the presence of synuclein aggregates and overt neurodegeneration and gliosis. Thus, by applying profiling, or “systems” approaches to rodent models of PD, we identified interesting disease related changes that pave the way for a better understanding of the earliest disease processes.