Neuroscience and Symptoms Related to the CADASIL Disease

Neuroscience and Symptoms Related to the CADASIL Disease

Katerina Ioannidou (Bioinformatics & Medical Informatics Team, Biomedical Research Foundation, Academy of Athens, Athens, Greece), Dimitrios Vlachakis (Bioinformatics & Medical Informatics Team, Biomedical Research Foundation, Academy of Athens, Athens, Greece), George Matsopoulos (School of Electrical and Computer Engineering, National Technical University of Athens, Athens, Greece) and Sophia Kossida (Bioinformatics & Medical Informatics Team, Biomedical Research Foundation, Academy of Athens, Athens, Greece)
DOI: 10.4018/ijsbbt.2013100102
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Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) disease belongs to the group of rare diseases. It is well established that Notch3 protein is primarily responsible for the development of the CADASIL syndrome. Herein, we attempt to shed light to the actual molecular mechanism underlying CADASIL syndrome via insights that we have from preliminary in silico and proteomics studies on the Notch3 protein, which is involved in many cancers and in particular lung and ovarian cancer. In this disease we always see accumulation of Granular Osmiophilic Material (GOM), which has been a hallmark for the final diagnosis based on electron microcopy (EM). Consequently, we present the regions of the brain that get affected by the disease and their functions. Finally, the symptoms of CADASIL are examined with reference to the neurological analysis that has preceded.
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Introduction

The ultimate goal of our research is to provide insights into the structural properties of the Notch3 protein that promotes the CADASIL syndrome. In order to achieve this, the 3D structural properties of the Notch3 protein must be analyzed. There is evidence that controlling Notch3 protein is very important for cancer progression. We know that Notch 3 affects stem cell maintenance, development and death via its control on cell survival and angiogenesis. There is also evidence that Notch3 cross-talks with other oncogenes that are very important in the anti-cancer research field. The Notch3 signaling pathway is ligand-induced, where a ligand docks and induces the exposure of the S2 domain within the negative regulatory region (NRR). Therefore inhibition of Notch3 using the knowledge derived from the CADASIL experiments may also lead to the development of a new anti-cancer strategy, comprising of novel Notch 3-specific inhibitor compounds.

Notch was first reported by T.H. Morgan almost a hundred years ago (Artavanis-Tsakonas & Muskavitch, 2010; Guruharsha et al., 2012; Louvi & Artavanis-Tsakonas, 2012). However, the first significant breakthrough came with Don Poulson in the 1930s (Poulsons, 1936). Poulson linked the embryonic phenotypes that he was observing to deletions in the chromosomes. One of those deletions was Notch, which is a minor X-linked mutation. The Notch3 is a receptor protein that is strategically positioned on the surface of smooth muscle cell very close to the local blood vessels. Following Poulson’s findings it was found that if Notch switches off and becomes inactive, epidermal precursors kick in that convert normal cells to neuroblasts (Artavanis-Tsakonas & Muskavitch, 2010; Guruharsha et al., 2012; Louvi & Artavanis-Tsakonas, 2012). Neuroblasts differentiate and produce embryos that have nervous system hypertrophy and epidermal structure deficiencies. Bill Welshon then studied the 3C7 region on the X chromosome, where Notch is located. It was then that a very detailed map of Notch mutations was first drawn. In flies Notch is affecting a series of biological characteristics, including the definition of boundaries between cells with developmental roles (Demerec, 1950; Go, et al., 1998). Overall it is well established that Notch activity influences differentiation, proliferation and apoptosis.

Notch has been linked mainly to three inherited diseases, one of which is CADASIL. An excess of 190 mutations of the Notch3 gene have been found to induce CADASIL. CADASIL is a hereditary disease affecting over middle-aged adults, leading them to disability and dementia. CADASIL stands for cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. It was first identified as a disease in 1993, even though there are records pointing back in 1955, when van Bogaert characterized CADASIL as the Binswanger disease (Artavanis-Tsakonas & Muskavitch, 2010; Guruharsha, et al., 2012; Louvi & Artavanis-Tsakonas, 2012). After a series of other patient incidences, CADASIL disease was linked to the Notch homolog 3 protein. The actual prevalence of the disease is unknown. However, CADASIL has been reported in more than five hundred families around the globe. The clinical manifestation of CADASIL can be described by five distinct symptoms. Those are: migraine with aura, subcortical ischemic events, mood disturbance, apathy and cognitive impairment. The symptoms can vary depending on patient age and progression of the syndrome (Artavanis-Tsakonas & Muskavitch, 2010; Guruharsha, et al., 2012; Louvi & Artavanis-Tsakonas, 2012).

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