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Combined Transcriptomic and Proteomic Analyses of Cerebral Frontal Lobe Tissue Identified RNA Metabolism Dysregulation as One Potential Pathogenic Mechanism in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

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Background: Cerebral small vessel disease (SVD) is an important cause of stroke and vascular cognitive impairment (VCI), leading to subcortical ischemic vascular dementia. As a hereditary form of SVD with early onset, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) represents a pure form of SVD and may thus serve as a model disease for SVD. To date, underlying molecular mechanisms linking vascular pathology and subsequent neuronal damage in SVD are incompletely understood.

Objective: We performed comparative transcriptional profiling microarray and proteomic analyses on post-mortem frontal lobe specimen from 2 CADASIL patients and 5 non neurologically diseased controls in order to identify dysregulated pathways potentially involved in the development of tissue damage in CADASIL.

Methods: Transcriptional microarray analysis of material extracted from frontal grey and white matter (WM) identified subsets of up- or down-regulated genes enriched into biological pathways mostly in WM areas. Proteomic analysis of these regions also highlighted cellular processes identified by dysregulated proteins.

Results: Discrepancies between proteomic and transcriptomic data were observed, but a number of pathways were commonly associated with genes and corresponding proteins, such as: “ribosome” identified by upregulated genes and proteins in frontal cortex or “spliceosome” associated with down-regulated genes and proteins in frontal WM.

Conclusion: This latter finding suggests that defective expression of spliceosomal components may alter widespread splicing profile, potentially inducing expression abnormalities that could contribute to cerebral WM damage in CADASIL.
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Keywords: CADASIL; pathomechanisms; proteomic; ribosome; spliceosome; transcriptomic

Document Type: Research Article

Publication date: October 1, 2019

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  • Current Neurovascular Research (CNR) provides a cross platform for the publication of scientifically rigorous research that addresses disease mechanisms of both neuronal and vascular origins in neuroscience. The journal serves as an international forum for the publication of novel and pioneering original work as well as timely neuroscience research reviews in the disciplines of cell developmental disorders, plasticity, and degeneration that bridge the gap between basic science research and clinical discovery. CNR emphasizes the elucidation of disease mechanisms, both cellular and molecular, which can impact the development of unique therapeutic strategies for neuronal and vascular disorders.
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