Dataset Information

Proteome analysis of microvessels from CADASIL patients

ABSTRACT: CADASIL, the most frequent and intensely studied monogenic SVD, is characterized by a severe pathology in the cerebral vasculature including the mutation-induced aggregation of the Notch3 extracellular domain (Notch3ECD) and the formation of protein deposits of insufficiently determined composition in the extracellular space of vessel walls. To advance our understanding of protein accumulation in CADASIL-affected tissue, we quantitatively determined the proteome of cerebral vessels isolated from patient and control autopsy samples (n = 6 for each group), obtaining 95 proteins with significantly increased abundance.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Microvessel

DISEASE(S): Cadasil

SUBMITTER: Stephan Mueller

LAB HEAD: Christof Haffner

PROVIDER: PXD009393 | Pride | 2018-08-03

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

Items per page:

1 - 5 of 13

Publications

CADASIL brain vessels show a HTRA1 loss-of-function profile.

Zellner Andreas A Scharrer Eva E Arzberger Thomas T Oka Chio C Domenga-Denier Valérie V Joutel Anne A Lichtenthaler Stefan F SF Müller Stephan A SA Dichgans Martin M Haffner Christof C

Acta neuropathologica 20180503 1

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and a phenotypically similar recessive condition (CARASIL) have emerged as important genetic model diseases for studying the molecular pathomechanisms of cerebral small vessel disease (SVD). CADASIL, the most frequent and intensely explored monogenic SVD, is characterized by a severe pathology in the cerebral vasculature including the mutation-induced aggregation of the Notch3 extracellular domai ...[more]

PMID: 29725820

Similar Datasets

Project description:While most cases of vascular dementia represent complex interactions between host genetics and environmental factors, mendelian forms of vascular dementia also exist. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a mendelian disease characterized by progressive vascular deterioration, cognitive deficits, and strokes. Mutations in the NOTCH3 receptor underlies the pathologies in CADASIL. NOTCH3 is primarily expressed in vascular smooth muscle cell (vSMC) and its’ expression is critical for differentiation and functional integrity of arterial vSMCs, albeit through unclear mechanism(s). To elucidate the contribution of NOTCH3 in the maintenance of cerebral vascular architecture and function, we performed micro-computed tomography (micro-CT) on the brains of aged Notch3-deficient animals. Micro-CT assessment of the cerebral vasculature architecture showed significant abnormalities including severe vessel dilation and tortuosity (dolicoectasia) of the middle cerebral artery and its branches in the Notch3-/- compared to aged-match controls. To identify the molecular pathway from NOTCH3 dysregulation to the observed cerebral vascular dysfunction, we performed single-cell RNASeq on cerebral arteries isolated from young (4w) and old (104w) Notch3-/- animals. Evaluation of the vSMC-specific transcriptomes indicated significant loss of proteins associated with muscle contraction and increased extracellular matrix production in animals that lack NOTCH3. Using a combination of immunofluorescence microscopy and in vitro functional assays, we confirmed that continued expression of Notch3 is a critical requirement for maintenance of vSMC contractile function. Impaired contractility also affected flow of cerebrospinal fluid in the parenchyma of Notch3-/- . MRI and behavioral assessments were performed in the Notch3-/- animals to elucidate the relationship between impaired vascular contractility to cognitive function. Taken together these findings link the molecular dysfunction of NOTCH3 through its regulation of vascular contractility and cerebral vessel architecture to altered neurological function and clarify the molecular pathways to cellular pathology of Notch3 driven dementias.

			Action	DRS
	Human_CAD_1.raw	Raw
	Human_CAD_2.raw	Raw
	Human_CAD_3.raw	Raw
	Human_CAD_4.raw	Raw
	Human_CAD_5.raw	Raw