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Abstract

A new mechanism, dubbed molecular misreading; the inaccurate conversion of genomic information into aberrant transcripts and mutant proteins (e.g. mutant ubiquitin B, UBB+1) was discovered. UBB+1 accumulate in the hallmarks (e.g. plaques and tangles) of sporadic Alzheimer and Down syndrome patients, but not in young non-demented controls. This was the cover story of Science 279, January 9th, 1998. The message is that UBB+1 contributes to neuronal dysfunctioning, e.g. by inhibiting the ubiquitin-proteasome system. Ubiquitin is a molecule that plays a role in a large number of tasks, for example the degradation of aberrant proteins, an important discovery, for which in 2004 the Nobel prize in Chemistry was awarded to three colleagues, including Ciechanover, who made the following remark about the Science paper: �Perhaps the most compelling evidence for the involvement of the ubiquitin-proteasome system in Alzheimer pathogenesis. The recent unraveling of the fascinating UBB+1 story by van Leeuwen suggests that we may soon see many more completely novel mechanisms involved in neuronal degeneration�. UBB+1 is an indicator for proteasomal dysfunction which shows up specifically in tauopathies but not in synucleinopathies (e.g. Parkinson�s disease). Recently UBB+1 was also detected in the hallmarks of polyglutamine diseases (e.g. intranuclear inclusions) and found to strongly contribute to aggregate formation and neuronal death (in vivo). Our new data implicate that AD starts in the brainstem with changes in the central regulation of respiration. Therefore we focus on interactions of hypoxia, oxidative stress, proteasomal inhibition, molecular chaperones and Aβ plaque load.

Biography

Fred W Van Leeuwen is a neuroscientist with over 200 peer-reviewed scientific papers to his name (Hirsch factor 48). His team works at the University Maastricht. He was trained as a neurobiologist and obtained his PhD degree in 1980. He worked at the Netherlands Institute for Brain Research of the Royal Netherlands Academy of Science and Arts in Amsterdam and moved to the University of Maastricht in 2007.