SNCA overexpression disturbs hippocampal gene expression trajectories in midlife.

Thomas Hentrich,Olaf Riess,Zinah Wassouf,Julia M. Schulze-Hentrich

doi:10.18632/aging.101691

Abstract

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.

Highlights

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]
The number of Differentially expressed gene (DEG) for 12-month-old TG mice housed in standard environment (SE) increased to 495, which were overrepresented for several pathways linked to SNCA pathology before, most significantly neuroinflammation signalling (Fig. 1B, Table S1)
Computational estimates of the underlying cell type composition neither indicated shifts between neuronal and glial cell populations for any of the experimental groups during that time frame (Fig. S1). These findings suggest an unfolding of events during 6 and 12 months of age that originate from the interference of persistent SNCA overexpression and dynamics of the system during midlife that resulted in observed disturbances in TG animals under standard conditions

Summary

Introduction

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]. The majority of synucleinopathies seemingly originates from a complex and still largely enigmatic interplay of genetic predisposition, age, and environmental factors. While hallmark clinical symptoms of PD and DLB patients are late-life progressive motor impairments, pre-motor phenotypes often surface decades earlier during midlife [6]. Increasing evidence suggests this time window to be critical for environmental factors to modulate disease unfolding as exercise and physical activity during midlife have been found to lower the risk for PD [7, 8] and dementia in elderly [9, 10]

Methods

Results

Conclusion