Objective: Understand the molecular principles and identify genetic drivers underlying and mitigating the preventative effects of environmental enrichment on the unfolding of Parkinson´s disease (PD) pathology.

Background: While genomic mutations and multiplications have been linked to rare familial forms of PD, the preponderance of PD cases cannot be explained by genetics alone and seems to occur sporadically. Moreover, age as well as environmental factors correlate with onset and progression of the disease. This multi-factorial interplay suggests a highly complex pathomechanism that has remained largely enigmatic.

Methods: A transgenic mouse model over-expressing the human wildtype SNCA gene was generated for this study and showed early non-motor symptoms of PD. Both wildtype (WT) and transgenic (TG) animals were exposed to either a standard (SE) or enriched environment (EE), the latter modeled by enhancing social and cognitive complexity and stimulating physical activity over a period of 12 months. RNA-Seq was used to profile gene expression in hippocampal tissue of all four experimental groups in order to (i) identify genes and cellular processes disturbed through SNCA-overexpression and to (ii) reveal effects on gene activity induced through the EE.

Results: Differentially expressed genes in transgenic animals housed in SE pointed to disturbances in synaptic processes and several other cellular pathways linked to SNCA before. Intriguingly, transgenic animals housed in EE were largely protected from these disturbances in gene activity. Bioinformatic analyses revealed specific transcription factors, kinases, and phosphatases that likely drove the observed protection by activating an array of downstream targets that counterbalanced the influence of the SNCA transgene. Together with first epigenetic data, we integrated these data to a system’s view of environmental protection and its mechanisms along the gene-environment axis in PD.

Conclusions: Our study identifies candidate genes and suggests potential cascades of activation underlying the protective effect of environmental enrichment in PD. We consider these efforts to be highly valuable in assessing whether changes in life style can delay or ameliorate PD symptoms in human, and whether these candidate genes offer opportunities to mimic the environmental influence towards much-needed novel therapies of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/physical-and-cognitive-stimulation-through-environmental-enrichment-prevents-early-molecular-pathology-in-a-parkinsons-disease-model/