Title: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)
Volume: 16
Issue: 5
Author(s): Marie-Françoise Ritz*, Paul Jenoe, Leo Bonati, Stefan Engelter, Philippe Lyrer and Nils Peters
Affiliation:
- Department of Biomedicine, Brain Tumor Biology Laboratory, University of Basel, and University Hospital of Basel, Hebelstrasse 20, 4031 Basel,Switzerland
Keywords:
CADASIL, transcriptomic, proteomic, pathomechanisms, spliceosome, ribosome.
Abstract:
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.
