Research Article: SNCA overexpression disturbs hippocampal gene expression trajectories in midlife

Date Published: December 13, 2018

Publisher: Impact Journals

Author(s): Thomas Hentrich, Zinah Wassouf, Olaf Riess, Julia M. Schulze-Hentrich.


Synucleinopathies like Parkinson’s disease and dementia with Lewy bodies originate from a complex and still largely enigmatic interplay of genetic predisposition, age, and environmental factors. While progressively declining motor functions hallmark late-life symptoms, first signs of the disease often surface already decades earlier during midlife. To better understand early disease stages with respect to the genetic, temporal, and environmental dimension, we interrogated hippocampal transcriptome data obtained during midlife for a mouse model overexpressing human SNCA, a pivotal gene in synucleinopathies, under different environments. To relate differentially expressed genes to human, we integrated expression signatures for aging and Parkinson’s disease. We identified two distinctive modes of age-dependent disturbances: First, cellular processes seemingly activated too early that reflected advanced stages of age and, second, typical longitudinal adaptations of the system that no longer occurred during midlife. Environmental enrichment prevented both disturbances modes despite persistent SNCA overload. Together, our results caution the view that expression changes characterising early stages of SNCA-related pathology reflect accelerated aging alone. Instead, we provide evidence that failure to undergo healthy adaptions during midlife represents a second origin of disturbances. This bimodal disturbance principle could inform therapeutic efforts to distinguish between preventive and restorative attempts to target the disease.

Partial Text

The pathology of synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) is characterized by increasing abnormal accumulation and aggregation of alpha-synuclein protein encoded by the SNCA locus [1]. Genetic studies further emphasize the role of SNCA as point mutations and genomic multiplications are linked to familial forms of PD in a gene dose-dependent manner [2–5]. Genetic SNCA defects, however, account for only a small fraction of cases. The majority of synucleinopathies seemingly originates from a complex and still largely enigmatic interplay of genetic predisposition, age, and environmental factors.

In this study, we examined expression changes in hippocampal transcriptome data of 6- and 12-month-old wildtype and SNCA-overexpressing mice to better understand interactions between the genetic, temporal, and environmental dimension in the unfolding of SNCA-related pathology. We identified expression disturbances previously linked to early stages of SNCA-related pathogenesis that emerged during midlife and originated from two distinctive interference modes (Fig. 6). Intriguingly, environmental enrichment rendered both modes ineffective, resulting in a near-normal transcriptome state despite persistent SNCA overexpression (Fig. 6).




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