Age-Related Dementia May Begin with Neurons' Inability to Rid Themselves of Unwanted Proteins

Newswise — BETHESDA, MD – March 5, 2013 -- A team of European scientists from the University Medical Center Hamburg-Eppendorf (UKE) and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) at the University of Cologne in Germany has taken an important step closer to understanding the root cause of age-related dementia. In research involving both worms and mice, they have found that age-related dementia is likely the result of a declining ability of neurons to dispose of unwanted aggregated proteins. As protein disposal becomes significantly less efficient with increasing age, the buildup of these unwanted proteins ultimately leads to the development and progression of dementia. This research appears in the March 2013 issue of the journal GENETICS.

“By studying disease progression in dementia, specifically by focusing on mechanisms neurons use to dispose of unwanted proteins, we show how these are interconnected and how these mechanisms deteriorate over time,” said Markus Glatzel, M.D., a researcher involved in the work from the Institute of Neuropathology at UKE in Hamburg, Germany. “This gives us a better understanding as to why dementias affect older persons; the ultimate aim is to use these insights to devise novel therapies to restore the full capacity of protein disposal in aged neurons.”

To make this discovery, scientists carried out their experiments in both worm and mouse models that had a genetically-determined dementia in which the disease was caused by protein accumulation in neurons. In the worm model, researchers in the lab of Thorsten Hoppe, Ph.D., from the CECAD Cluster of Excellence could inactivate distinct routes used for the disposal of the unwanted proteins. Results provided valuable insight into the mechanisms that neurons use to cope with protein accumulation. These pathways were then assessed in young and aged mice. This study provides an explanation of why dementias exponentially increase with age. Additionally, neuron protein disposal methods may offer a therapeutic target for the development of drugs to treat and/or prevent dementias.

“This is an exciting study that helps us understand what’s going wrong at a cellular level in age-related dementias,” said Mark Johnston, Ph.D., Editor-in-Chief of the journal GENETICS. “This research holds possibilities for future identification of substances that can prevent, stop, or reverse this cellular malfunction in humans.”

CITATION: Schipanski, Angela, Sascha Lange, Alexandra Segref, Aljona Gutschmidt, David A. Lomas, Elena Miranda, Michaela Schweizer, Thorsten Hoppe, and Markus GlatzelA Novel Interaction between Aging and ER Overload in a Protein Conformational DementiaGenetics March 2013, 193: 865-876.

FUNDING: This work is supported by grants of the Deutsche Forschungsgemeinschaft (especially the FOR885 to M.G. and T.H., the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) to T.H. and GRK1459 to M.G.), the Medical Research Council (UK) to D.L., the Hans und Ilse Breuer Foundation to S.L., the Leibniz Center Infection Graduate School (Model systems for infectious diseases), and the Landesexzellenzinitiative of Hamburg (SDI-LEXI) to M.G.

ABOUT GENETICS: Since 1916, GENETICS has covered high quality, original research on a range of topics bearing on inheritance, including population and evolutionary genetics, complex traits, developmental and behavioral genetics, cellular genetics, gene expression, genome integrity and transmission, and genome and systems biology. GENETICS, a peer-reviewed, peer-edited journal of the Genetics Society of America is one of the world's most cited journals in genetics and heredity.

ABOUT GSA: Founded in 1931, the Genetics Society of America (GSA) is the professional membership organization for scientific researchers, educators, bioengineers, bioinformaticians and others interested in the field of genetics. Its nearly 5,000 members work to advance knowledge in the basic mechanisms of inheritance, from the molecular to the population level. The GSA is dedicated to promoting research in genetics and to facilitating communication among geneticists worldwide through its conferences, including the biennial conference on Model Organisms to Human Biology, an interdisciplinary meeting on current and cutting edge topics in genetics research, as well as annual and biennial meetings that focus on the genetics of particular organisms, including C. elegans, Drosophila, fungi, mice, yeast, and zebrafish. GSA publishes GENETICS, a leading journal in the field and an online, open-access journal, G3: Genes|Genomes|Genetics. For more information about GSA, please visit www.genetics-gsa.org. Also follow GSA on Facebook at facebook.com/GeneticsGSA and on Twitter @GeneticsGSA.