Fred van Leeuwen, professor at the Maastricht University in the Netherlands, passed away Wednesday, January 13. Van Leeuwen is best known for his discovery of a faulty transcription mechanism, dubbed “molecular misreading,” in the neurons of people who had sporadic Alzheimer’s disease. He frequently contributed to Alzforum.
Van Leeuwen’s seminal paper made the cover of Science in 1998 (van Leeuwen et al., 1998). He found that despite having normal DNA, neurons in some people ended up with fewer nucleotides in mRNAs for amyloid precursor protein (APP) and ubiquitin B (UBB). These deletions caused a 1-nucleotide frameshift that led to premature truncation of the two proteins (Apr 1999 news; van Leeuwen et al., 2000). The shortened proteins, dubbed APP+1 and UBB+1 to denote the frameshift, accumulated in plaques or clogged the proteasome, respectively (Dec 2004 conference news). Van Leewen’s work was featured in one of the earliest Alzforum webinars (May 1998 webinar).
In cultured neurons, UBB+1 triggered cell death (De Vrij et al., 2001). APP+1 turned out to be secreted from neurons, but much less turned up in the CSF of people with Alzheimer’s compared to healthy controls, suggesting problems secreting the protein (Hol et al., 2003). Neuronal accumulations of APP+1 and UBB+1 were found in people with frontotemporal dementia, Pick's disease, progressive supranuclear palsy, and Huntington’s, but not Parkinson’s (van Leeuwen et al., 2006; Dennissen et al., 2010).
Van Leeuwen created UBB+1 transgenic mice; they had dysfunctional proteasomes in their brains and performed poorly on memory tests (Fischer et al., 2009). His lab crossed the UBB+1 mice with the APPPS1 mouse model of amyloidosis. Paradoxically, the offspring had smaller plaque loads than their parents, but still had behavioral deficits (Verheijen et al., 2018).
Van Leeuwen began his research career at the Netherlands Institute for Brain Research in 1974. He remained there for 32 years until he moved to Maastricht University in 2007. We invite friends and colleagues to celebrate his life by emailing tributes to email@example.com for posting on Alzforum.—Chelsea Weidman Burke
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- van Leeuwen FW, de Kleijn DP, van den Hurk HH, Neubauer A, Sonnemans MA, Sluijs JA, Köycü S, Ramdjielal RD, Salehi A, Martens GJ, Grosveld FG, Peter J, Burbach H, Hol EM. Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. Science. 1998 Jan 9;279(5348):242-7. PubMed.
- van Leeuwen FW, Fischer DF, Kamel D, Sluijs JA, Sonnemans MA, Benne R, Swaab DF, Salehi A, Hol EM. Molecular misreading: a new type of transcript mutation expressed during aging. Neurobiol Aging. 2000 Nov-Dec;21(6):879-91. PubMed.
- De Vrij FM, Sluijs JA, Gregori L, Fischer DF, Hermens WT, Goldgaber D, Verhaagen J, Van Leeuwen FW, Hol EM. Mutant ubiquitin expressed in Alzheimer's disease causes neuronal death. FASEB J. 2001 Dec;15(14):2680-8. PubMed.
- Hol EM, van Dijk R, Gerez L, Sluijs JA, Hobo B, Tonk MT, de Haan A, Kamphorst W, Fischer DF, Benne R, Van Leeuwen FW. Frameshifted beta-amyloid precursor protein (APP+1) is a secretory protein, and the level of APP+1 in cerebrospinal fluid is linked to Alzheimer pathology. J Biol Chem. 2003 Oct 10;278(41):39637-43. PubMed.
- Van Leeuwen FW, van Tijn P, Sonnemans MA, Hobo B, Mann DM, Van Broeckhoven C, Kumar-Singh S, Cras P, Leuba G, Savioz A, Maat-Schieman ML, Yamaguchi H, Kros JM, Kamphorst W, Hol EM, De Vos RA, Fischer DF. Frameshift proteins in autosomal dominant forms of Alzheimer disease and other tauopathies. Neurology. 2006 Jan 24;66(2 Suppl 1):S86-92. PubMed.
- Dennissen FJ, Kholod N, Steinbusch HW, Van Leeuwen FW. Misframed proteins and neurodegeneration: a novel view on Alzheimer's and Parkinson's diseases. Neurodegener Dis. 2010;7(1-3):76-9. PubMed.
- Fischer DF, van Dijk R, van Tijn P, Hobo B, Verhage MC, van der Schors RC, Li KW, van Minnen J, Hol EM, Van Leeuwen FW. Long-term proteasome dysfunction in the mouse brain by expression of aberrant ubiquitin. Neurobiol Aging. 2009 Jun;30(6):847-63. PubMed.
- Verheijen BM, Stevens JA, Gentier RJ, van 't Hekke CD, van den Hove DL, Hermes DJ, Steinbusch HW, Ruijter JM, Grimm MO, Haupenthal VJ, Annaert W, Hartmann T, van Leeuwen FW. Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model. Neurobiol Aging. 2018 Dec;72:62-71. Epub 2018 Aug 18 PubMed.
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