- Juenemann K, Jansen AHP, van Riel L, Merkx R, Mulder MPC, An H, Statsyuk A, Kirstein J, Ovaa H, Reits EA, Dynamic recruitment of ubiquitin to mutant huntingtin inclusion bodies. SCI REP-UK 2018;8 (1):1405 [PubMed]
- Jansen AHP, van Hal M, Op den Kelder IC, Meier RT, de Ruiter AA, Schut MH, Smith DL, Grit C, Brouwer N, Kamphuis W, Boddeke HWGM, den Dunnen WFA, van Roon WMC, Bates GP, Hol EM, Reits EA, Frequency of nuclear mutant huntingtin inclusion formation in neurons and glia is cell-type-specific. GLIA 2017;65 (1):50-61 [PubMed]
- Wiemhoefer A, Stargardt A, van der Linden WA, Renner MC, van Kesteren RE, Stap J, Raspe MA , Tomkinson B, Kessels HW, Ovaa H, Overkleeft HS, Florea B, Reits EA, Tripeptidyl Peptidase II Mediates Levels of Nuclear Phosphorylated ERK1 and ERK2. MOL CELL PROTEOMICS 2015;14 (8):2177-2193 [PubMed]
- Schipper-Krom S, Juenemann K, Jansen AH, Wiemhoefer A, van den Nieuwendijk R, Smith DL, Hink MA, Bates GP, Overkleeft H, Ovaa H, Reits E, Dynamic recruitment of active proteasomes into polyglutamine initiated inclusion bodies. FEBS LETT 2014;588 (1):151-159 [PubMed]
- Juenemann K, Schipper-Krom S, Wiemhoefer A, Kloss A, Sanz Sanz A, Reits EAJ, Expanded Polyglutamine-containing N-terminal Huntingtin Fragments Are Entirely Degraded by Mammalian Proteasomes. J BIOL CHEM 2013;288 (38):27068-27084 [PubMed]
2008 NWO VIDI personal grant to study and improve the clearance of polyQ fragments and aggregates
2004 NWO VENI personal research grant to study protein and peptide clearance
2000 Antonie van Leeuwenhoekprijs (award of the Netherlands Cancer Institute for a high-potential researcher)
Doctorate University: University Leiden, cum laude 25-10-2001
Supervisor: Prof. Dr. Jacques J. Neefjes
Title of thesis: Dynamics of Antigen Processing in Living Cells
IMPROVING PROTEIN DEGRADATION IN HUNTINGTON’S DISEASE
Huntington’s Disease (HD) is an dominant inherited neurodegenerative disorder with the combined symptoms of Alzheimer, Parkinson and ALS. HD is caused by a mutation in the gene encoding the huntington protein. Due to the expansion of the CAG repeat in the gene the encoded huntington protein had an extended repeat of glutamine amino acids (polyQ) in the protein. Due to the repeat expansion the mutant Htt protein (mHtt) aggregates in neuronal cells, leading to their dysfunction, with consequences for memory and movement and psychiatric problems. Following the first symptoms the patient will live on average 15-17 years.
Improving the degradation of these mHtt fragments prior to aggregation would be a therapeutic strategy for this devastating disease for which there is no cure.
The main protein degradation machinery in cells is the Ubiquitin-Proteasome System (UPS) which is present in both the cytoplasm and nucleus. It degrades both short-lived, misfolded proteins and long-lived proteins that are mainly targeted for degradation via ubiquitination. The role of the UPS in HD is however controversial since UPS impairment has been observed in various HD models, which could be due to sequestration of proteasomes into aggregates (inclusion bodies, IB) that are initiated by mHTT. In addition, proteasomes may even be unable to cleave within the polyglutamine (polyQ) expansion in mHTT that is caused by the CAG repeat expansion in the mutated gene. Proteasomes may become clogged by these fragments or release polyQ peptides when polyQ-expanded proteins are inefficiently degraded.
Our research group have addressed various research questions with relation to the UPS and its role in the degradation of mHtt.
Prof. dr. E.A.J. Reits
Dr. N.N. van der Wel
Dr. A. Bury
Dr. K.A. Sap
Dr. S. Schipper-Krom
Dr. M. Tohti
K.W. Geijtenbeek MSc
E.M. Scutigliani MSc
Drs. J. Janzen MSc
- Membership of medical or scientific committee, Vereniging van Huntington, WAR
- Membership of medical or scientific committee, Dutch Huntington Disease Research Network, Chair
- Membership of medical or scientific committee, Nederlandse Vereniging voor de Microscopie, Secretaris
- Birmingham Women's Hospital
- CHDI Foundation, Inc., c/o CHDI Management, Inc.
- KWF Kankerbestrijding
- Stichting AMC Foundation (Vrijgesteld)
- Stichting Immuno Valley