Objective: Understanding early, and therefore often subtle, disease processes in Parkinson’s disease (PD) is essential for 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 already progressed beyond repair. To investigate if measures of metabolite changes can help detect early disease processes, and thus open the way to biomarker and/or target identification, we investigated metabolic profiles in the brain of various genetic and induced PD models.

Background: Different aspects or disease stages of PD can be modeled in rodents by genetic (transgenic, knockin or – out) of PD-associated genes, or, as demonstrated recently, by inducing spreading of misfolded synuclein through administration of a synuclein seeding source. We analysed genetic models (LRRK2 knockin, SNCA transgenic, DJ-1 Knockout, and crosses thereof), and induced models (spreading of synuclein induced by intrastriatal injection of recombinant synuclein fibrils in mice, or intravagal injection of a viral construct expressing human synuclein in rats).

Methods: We investigated metabolic profiles in brain extracts of these models using a Gas-Chromatography/Mass-Spectrometry platform, and compared them with behavioural and neuropathological measures. We analysed changes in individual metabolites, as well as, using Principal Component Analysis and supervised machine learning, shifts in metabolite populations and the known cellular pathways they are associated with.

Results: By analyzing the brains of these models at different ages or different points after synuclein spreading induction, we drew out metabolic shifts that coincided with subtle, early motor disturbances (genetic models), and were, for the most part, independent of neuropathological changes such as the presence of synuclein aggregates and overt neurodegeneration (induced models). Some metabolites, many of them still unknown, appeared to correlate with motor performance in genetic models.

Conclusions: Metabolic profiling offers a new window in brain function in health and disease. By applying this approach in rodent models of PD, we identified interesting disease stage-related changes in metabolites that pave the way for a better understanding of early disease processes.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/brain-metabolic-profile-changes-reflect-subtle-pathological-alterations-in-different-murine-models-of-parkinsons-disease/