Huntington Disease proteostasis group

Huntington’s Disease (HD) is caused by the accumulation and aggregation of mutant huntington (mHTT) fragments in neuronal cells. We focus on improving selective degradation of mHTT by the ubiquitin-proteasome system, using a combination of advanced microscopy, proteomics, peptide chemistry and biochemistry to understand and manipulate degradation of mHTT in 2D and 3D cell models. Recent developments include high-content cellular screening models for compound and genetic screening, and the usage of human-derived HD iPSC models to screen and validate novel therapeutic strategies.

Team leaders

Eric Reits

Professor in Cellular Imaging, PI at the department of Medical Biology Amsterdam UMC location AMC

We demonstrated that the UPS remains functional in neuronal cells during HD and is even capable to efficiently degrade mutant huntingtin when ubiquitinated and targeted to the proteasome, but that the mutation in mHTT alters HTT ubiquitination and turnover. Following the identification of involved (de)ubiquitination enzymes we are currently working on different strategies to improve HTT degradation, and expanding these strategies to SpinoCerebellar Ataxia’s including SCA1 and SCA3. Ongoing activities in the HD research community include coordination of the recently awarded NWO NWA-ORC consortium CureQ: Predict, Delay & Cure polyglutamine(Q) caused neurodegeneration, which will form a unique network of all Dutch HD scientists, neurologists, biotech and patient foundations, and which will enable a unified approach to use iPSC models for improved diagnostics and therapy. In addition, I am chair of the Dutch HD research network, member of the scientific advisory board of the Dutch HD patient foundation, and co-founder of the Campagneteam Huntington to raise awareness for HD in the Dutch society and raise money for HD research groups.

As a cell biologist I use advanced microscopy, proteomics, peptide chemistry and biochemistry to study the role of the UPS in HD. We use advanced microscopy for various approaches, and I am head of the microscopy & flow core facility Amsterdam UMC/LCAM-AMC, secretary of the Dutch microscopy society, and chair of the NWO large research infrastructure NL-Biolmaging-AM: A top-level large-scale distributed advanced microscopy infrastructure for the Netherlands. As coordinator of the UvA biomedical mastertrack ‘Cell Biology and Advanced Microscopy’ I train master students in microscopy techniques and applications including HD research, as well as coordinating other teaching courses for bachelor, master and PhD students on the crossroads of microscopy and HD.