Thanks to funding of the ZonMw Open Competition, a total of six research projects will get started in which Amsterdam Neuroscience researchers are involved. The topics are very diverse, ranging from optimizing the treatment in ADHD to the molecular basis of memory. Each research team receives an average of 750,000 euros. Below, we showcase the projects of the two complementary research programs Neurodegeneration and Cellular & Molecular Mechanisms.

Selective mutant huntington lowering using a ubiquitin toolbox to identify and manipulate involved enzymes

Professor Eric Reits together with Leiden UMC

Huntington’s Disease (HD) is an inherited neurodegenerative disorder hallmarked by the symptoms of Alzheimer, Parkinson and ALS. The disease is caused by a genetic mutation in the DNA resulting in an aggregation-prone mutant huntington protein in the brain. There is no cure to delay or prevent HD. Recently, we showed that the garbagemen in the cell responsible for recycling old and incorrect proteins are still functional in HD, but that recognition and marking for degradation of the mutant huntingtin protein is inefficient. By combining the expertise’s of two research groups we aim to identify and manipulate enzymes involved, defining their working mechanisms and specificity in cultured human neuronal cells, and identify strategies to improve their effectiveness towards the mutant huntington protein. Improving degradation of the mutant protein prior to aggregation represents a novel therapeutic strategy to delay or prevent onset of this devastating disease.

Tau-induced dysregulation of the Integrated Stress Response in memory engram cells

Associate Professor Wiep Scheper, dr. Michel van den Oever, dr. Priyanka Rao-Ruiz

Memory loss occurs during Alzheimer's disease. Clumping of the protein tau accompanies memory loss, but it is not known how tau affects memory. Memory is stored by a small group of brain cells, so-called engram cells. Memories are formed and retrieved by changes in the levels of specific proteins. An important player in this process is the "Integrated Stress Response" which regulates the levels of proteins. This project will investigate which proteins are regulated by this response in engram cells during memory formation and retrieval. In addition, it will be studied whether tau clumps cause memory loss by disrupting these processes in engram cells. The results of this project provide insight into the molecular basis of memory and how this is disrupted in Alzheimer's disease.