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| First Name: | Fred | | Last Name: | van Leeuwen | | Title: | Dr. | | Advanced Degrees: | PhD | | Affiliation: | University Maastricht | | Department: | Cellular Neuroscience | | Street Address 1: | Universiteitssingel 50 | | City: | Maastricht | | Zip/Postal Code: | 6200 MD | Country/Territory: | Netherlands | | Phone: | 31 20 3881044 | | Fax: | 31 20 3671096 | | Email Address: |  |
Disclosure:
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View all comments by Fred van Leeuwen
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Polyglutamine Disorders (Huntington's, etc.), Alzheimer Disease, Prion Diseases, Neuromuscular Disorders (ALS, etc.), Aging Process, Neurodevelopmental Disorders (Down syndrome, etc.), Parkinson Disease, Tauopathies
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A-beta PP/A-beta, Animal Models, Apoptosis/Cell cycle, Neuroimmunology, Chemistry/Pharmacology, Oxidative Stress, DNA microarrays, Signal transduction, Stem cells, Genetics, Microscopy, Molecular and Cell biology, Neurobiology, Neuropathology, Neurotransmission, Protein structure/chemistry, Proteomics, Electrophysiology, Tau/Cytoskeleton
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Dr. F.W. van Leeuwen is a neuroscientist with over 100 peer-reviewed scientific papers to his name. His team works at the Netherlands Institute for Neuroscience (formerly the Netherlands Institute for Brain Research) in Amsterdam, which is an institute of the Royal Netherlands Academy of Arts and Sciences. He was trained as a neurobiologist and obtained his PhD degree in 1980.
After branching out into the field of molecular neurobiology in the nineties, he discovered 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). These appeared to be present 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 the mutant proteins accumulate and contribute to neuronal dysfunctioning, e.g. by inhibiting the ubiquitin-proteasome system. This article has been named a “milestone paper”, and Dr. van Leeuwen has been invited to participate in an Alzheimer-100 book because it was 100 years ago that Dr. Alzheimer published his first article on the disease.
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 publication by van Leeuwen: “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” (Neuron 40, 427 ff, 2003). 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). A US patent was obtained on this discovery (# 5,958,684).
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Science 279, 242ff, 1998 and numerous subsequent papers on misframed proteins, in particular ubiquitin and the ubiquitin-proteasome system that have appeared in the peer reviewed literature( see pubmed). |
No effective treatment at all |
Not really. I am afraid that the disease is to complex.
A link between the ubiquitin-proteasome system and Abeta has been shown and opens new horizons for straightforward (Song et al., Mol. Cell 12, 553ff, 2003, Gong et al., Cell 126,775ff, 2006). |
To identify the main players in the ubiquitin-proteasome system (around 1000 candidates are available !) and to validate their contribution to AD and other conformational diseases. |
An efficient ubiquitin-proteasome system (UPS)is of utmost importance to gaurantee cellular homeostasis. |
More research in the UPS. At the last AD meeting there was hardly any contribution on this topic.This is curious as the "ubiquitin family" (See CSH symposia) belongs to those that grow very rapid. It is "Time for the ubiquitin-proteasome system"(see also my comments on this site!). Also the studies on the autopaghy-lysosomal system by collegues like Nixon and Cuervo need to be implemented much more.
This is still an open niche!!!!!!! |
I am appointed here at Maastricht University |
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