Membralin Protein Discovered to be Crucial in Alzheimer's Pathogenesis
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Alterations in the Expression of a Specific Gene Linked to Alzheimer’s Disease

The development of Alzheimer’s is associated with numerous factors involving both genetic and non-genetic risk factors with the latter likely being mediated by epigenetic mechanisms. Now, a collaborative team of scientists in Switzerland and Spain have suggested that a particular gene known as peptidase M20-domain-containing protein 1 (PM20D1) has a strong role to play in AD.

Over the last seven years, we have created a detailed map of the epigenetic alterations that occur in the brain of people affected by Alzheimer’s and other dementias such as those associated with the so-called Lewy bodies or Parkinson’s disease. That allowed us to collaborate with Dr Johannes Gräff’s group in Lausanne, who noticed how one of the molecular lesions we had discovered was caused by inheriting a variation in the DNA sequence”– states Dr. Manel Esteller, co-author of the Nature Medicine study.

This variation is associated with the loss of activity of a neuroprotective gene called PM20D1; whoever possesses the variation has a greater probability of suffering from Alzheimer’s disease, so people carrying these variants could be excellent candidates for clinical prevention trials of the disease in the future“- adds the IDIBELL researcher.

Additional investigation of publicly available DNA methylation data additionally identified PM20D1 hypermethylation in AD patients.  Subsequent SNP studies suggested that PM20D1 hypermethylation is related with AD in those who carry two particular SNPs, rs708727 and rs960603, which can be both found in almost 85 percent of AD cases.  Genetic analysis of human brain cortex samples demonstrated an allele-dependent correlation between the dual SNP haplotype and PM20D1 DNA methylation.

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The results obtained demonstrate the need for international scientific collaboration, mixing the different areas of experience in epigenetics, genetics, bioinformatics and neurosciences of each group. We are looking at an example of the usefulness of multidisciplinary research to tackle diseases as complex and devastating as dementia,” concludes Esteller.