NeuroGeM, a knowledgebase of genetic modifiers in neurodegenerative diseases

Abstract

BackgroundNeurodegenerative diseases (NDs) are characterized by the progressive loss of neurons in the human brain. Although the majority of NDs are sporadic, evidence is accumulating that they have a strong genetic component. Therefore, significant efforts have been made in recent years to not only identify disease-causing genes but also genes that modify the severity of NDs, so-called genetic modifiers. To date there exists no compendium that lists and cross-links genetic modifiers of different NDs.DescriptionIn order to address this need, we present NeuroGeM, the first comprehensive knowledgebase providing integrated information on genetic modifiers of nine different NDs in the model organisms D. melanogaster, C. elegans, and S. cerevisiae. NeuroGeM cross-links curated genetic modifier information from the different NDs and provides details on experimental conditions used for modifier identification, functional annotations, links to homologous proteins and color-coded protein-protein interaction networks to visualize modifier interactions. We demonstrate how this database can be used to generate new understanding through meta-analysis. For instance, we reveal that the Drosophila genes DnaJ-1, thread, Atx2, and mub are generic modifiers that affect multiple if not all NDs.ConclusionAs the first compendium of genetic modifiers, NeuroGeM will assist experimental and computational scientists in their search for the pathophysiological mechanisms underlying NDs. http://chibi.ubc.ca/neurogem.

Ataxin-2 (Atxn2)-Knock-Out Mice Show Branched Chain Amino Acids and Fatty Acids Pathway Alterations

“…Neurodegenerative processes known as Spino-cerebellar Ataxia type 2 (SCA2), the motor neuron degeneration Amyotrophic Lateral Sclerosis (ALS13), Frontotemporal dementia, Supranuclear palsy, or Levodopa-responsive Parkinsonism can be triggered by this mechanism (32)(33)(34)(35)(36)(37)(38)(39). In Drosophila melanogaster flies, the Ataxin-2 ortholog dATX2 was shown to act as a generic modifier gene that affects multiple if not all neurodegenerative disorders (40). The protein interactions between ATXN2 and several other disease proteins of neurodegenerative disorders (41) and the similarity of atrophy patterns between these polyglutamine expansion diseases suggests a common molecular pathomechanism among these diverse neurodegenerative disorders (42).…”

Categorizer: a tool to categorize genes into user-defined biological groups based on semantic similarity

“…In order to demonstrate the functionality of Categorizer, we first analyzed the enrichment of specific categories in a set of genes that have been identified as genetic modifiers in Drosophila models of Huntington’s disease (HD). The data was compiled from NeuroGeM, a database of genetic modifiers of neurodegenerative diseases including HD, Alzheimer’s, Parkinson’s, Amyotrophic lateral sclerosis, and several Spinocerebellar ataxia types [ 28 , 29 ]. Modifiers are genes that are capable of modulating disease phenotypes; in this case the neuronal cell death caused by protein aggregation.…”

Genetic Modifiers and Rare Mendelian Disease

“…This could be because most common diseases are often non-Mendelian complex disorders, which are not included in OMIM, as well as the nature of GWAS results. NeuroGeM is one of the earliest databases on genetic modifiers specific to Neurodegenerative disorders [54]. The database was built by combining knowledge gained from Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae resources.…”