SNP and Structural Study of the Notch Superfamily Provides Insights and Novel Pharmacological Targets against the CADASIL Syndrome and Neurodegenerative Diseases

• Published in: Genes 2024-04, Vol.15 (5), p.529
• Main Authors: Papageorgiou, Louis, Papa, Lefteria, Papakonstantinou, Eleni, Mataragka, Antonia, Dragoumani, Konstantina, Chaniotis, Dimitrios, Beloukas, Apostolos, Iliopoulos, Costas, Bongcam-Rudloff, Erik, Chrousos, George P, Kossida, Sofia, Eliopoulos, Elias, Vlachakis, Dimitrios
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Analysis; Angiogenesis; Ataxia; Brain research; CADASIL; CADASIL - genetics; CADASIL - metabolism; CADASIL - pathology; Cancer; Cell cycle; Cell death; Cell interactions; Cell receptors; Central nervous system; Chromosomes; Dementia; Developmental plasticity; Disease; Embryogenesis; Epidermal growth factor; Evolutionary conservation; Gene mutations; Genes; Genetic aspects; Genotype & phenotype; Health aspects; Humans; Insects; Ischemia; Ligands; Methods; Molecular modelling; Mutagenesis; Mutation; Nervous system; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurogenesis; Notch protein; Notch3 protein; Pathogenesis; Pharmacology, Experimental; Physiological aspects; Polymorphism, Single Nucleotide; Protein structure; Proteins; Receptor, Notch3 - genetics; Receptor, Notch3 - metabolism; Receptors, Notch - genetics; Receptors, Notch - metabolism; Signal Transduction; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Smooth muscle; Stem cells; Synaptic plasticity; Synaptogenesis
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes15050529

The evolutionary conserved Notch signaling pathway functions as a mediator of direct cell-cell communication between neighboring cells during development. Notch plays a crucial role in various fundamental biological processes in a wide range of tissues. Accordingly, the aberrant signaling of this pathway underlies multiple genetic pathologies such as developmental syndromes, congenital disorders, neurodegenerative diseases, and cancer. Over the last two decades, significant data have shown that the Notch signaling pathway displays a significant function in the mature brains of vertebrates and invertebrates beyond neuronal development and specification during embryonic development. Neuronal connection, synaptic plasticity, learning, and memory appear to be regulated by this pathway. Specific mutations in human Notch family proteins have been linked to several neurodegenerative diseases including Alzheimer's disease, CADASIL, and ischemic injury. Neurodegenerative diseases are incurable disorders of the central nervous system that cause the progressive degeneration and/or death of brain nerve cells, affecting both mental function and movement (ataxia). There is currently a lot of study being conducted to better understand the molecular mechanisms by which Notch plays an essential role in the mature brain. In this study, an in silico analysis of polymorphisms and mutations in human Notch family members that lead to neurodegenerative diseases was performed in order to investigate the correlations among Notch family proteins and neurodegenerative diseases. Particular emphasis was placed on the study of mutations in the Notch3 protein and the structure analysis of the mutant Notch3 protein that leads to the manifestation of the CADASIL syndrome in order to spot possible conserved mutations and interpret the effect of these mutations in the Notch3 protein structure. Conserved mutations of cysteine residues may be candidate pharmacological targets for the potential therapy of CADASIL syndrome.