The teams consisted of researchers and clinicians from the Functional Genomics department of Vrije Universiteit Amsterdam, Human Genetics department of Amsterdam UMC, Amsterdam Neuroscience, Radboud UMC, University of Antwerp, and Antwerp University Hospital, as well as family members of STXBP1 patients. Each team biked more than eighty kilometers to the mid-point in Dordrecht, halfway between the labs of Amsterdam and the labs of Antwerp. In Dordrecht, all bikers were welcomed by supporters, family members of patients and colleagues.

We would like to thank all cyclists for their great achievement, the supporters for their enthusiasm and the sponsors for their donations. Especially Amsterdam Neuroscience for their generous donation of € 2.000,00! It has been heartwarming to see the overwhelming support for our cause. In total we raised € 6.359,00 and Penn State University will double this amount.

All donations have been transferred to the Million Dollar bike ride organization in the United States (team STXBP1). The Penn Medicine Orphan Disease Center will distribute the funds to the international scientific community through grant proposal applications. They will monitor and manage progress of the science and spending of the funds.

See the MDBR website for more information.

PSP and FTDs are part of a class of debilitating neurodegenerative diseases that may shorten a person’s lifespan, and for which no current treatments exist. The research program by van der Kant, is one out of four groundbreaking research projects funded through the Tauopathy Challenge Workshop, that will serve as building blocks toward ongoing efforts to find treatments and a cure for these diseases, known as primary tauopathies.

Work in the van der Kant lab focuses on examining how cholesterol, or other lipids, contribute to the tau pathology in PSP and FTD, knowing that recent studies have shown that excess levels of cholesterol in the brain can drive the build-up of tau. Dr. van der Kant will map how lipid metabolism in different iPSC-derived brain cell types is altered in these diseases, and how this might contribute to neuroinflammation. The project will help provide a better understanding of the early processes that drive PSP and FTDs.

Funding is awarded through the 2024 Tauopathy challenge workshop, which was held to close gaps in understanding and address current research challenges in primary tauopathies, such as Frontotemporal Dementias and Progressive Supranuclear Palsy. Funding was made available through the Rainwater Charitable Foundation in collaboration with the Aging Mind Foundation and the CurePSP foundation.

More information can be found here: https://rainwatercharitablefoundation.org/the-rainwater-charitable-foundation-curepsp-and-aging-mind-foundation-announce-2-million-in-grants-to-fund-innovative-research-projects-from-the-tauopathy-challenge-workshop/

Dr. Scheper, trained as an RNA biologist at Utrecht University, started working on the export of misfolded proteins from the endoplasmic reticulum during her time at Cambridge University, UK, and developed a strong research program in Amsterdam that investigates the role of proteostasis in neurodegenerative disorders such as Alzheimer’s disease, frontotemporal dementia and Parkinson’s disease. Since 2013, Dr. Scheper is principal investigator at FGA, and has built a multidisciplinary team and a prominent international reputation in the field, with excellent publications and strong external funding.  Dr. Scheper is also a familiar face in national media for outreach activities, laymen talks and fundraisers.

The purpose of the new chair is to initiate and conduct research to gain and deepen understanding of the role of proteostatic stress mechanisms in the pathogenesis of neurodegenerative diseases. This insight will lead to the identification of new targets for therapeutic intervention and associated biomarkers for therapy monitoring. Additionally, the chair focuses on the utilization of the results of this research through valorization towards the industry as well as science communication towards the general public.

Learn more about her research at her CNCR research page: https://cncr.nl/research-team/molecular_neurodegeneration_/ 

 

Dorret Boomsma received her two Master degrees in 1983 cum laude – one from the VU University in Amsterdam, in Psychophysiology and one from the University of Colorado, US in Behavior Genetics. After receiving her PhD cum laude from the VU in 1992 on the quantitative genetics of cardiovascular disease, she was appointed as an assistant professor at the VU University in Amsterdam, where she became the head of the Department of Biological Psychology in 1994.

Together with Prof Ko Orlebeke, Dorret Boomsma founded the Netherlands Twin Registry (NTR) in 1986, which currently consists of over 75,000 twins and their family members. The NTR has been and still is a tremendous success and an invaluable resource for the study of genetic and environmental influences on human nature, not only serving Dutch scientists, but facilitating worldwide collaborations. In thousands of scientific publications this resource has now been used, and Dorret’s work has delivered significant contributions to a broad spectrum of human behavior and disease, going from charting the relative influence of genes and environment to pinpointing the most likely causal genes using genomewide association tools and biomedical samples.

Dorret’s work has been lauded both nationally and internationally. She received numerous awards and prizes, including an advanced grant from the European Research Council (2008), the Ming Tsuang Life Time achievement award from the International Society of Psychiatric Genetics (2022), and an Honorary doctorate from the University of Helsinki Medical School (2022), Finland. In 2001 Dorret Boomsma received the Dutch Spinozapremie, which is said to be the Dutch equivalence of the Nobel Prize, recognizing her position as a top scientist.

The Department of Complex Trait Genetics is honored to be joined by Dorret Boomsma, she brings in a lifetime of scientific knowledge on quantitative and behavior genetics, an invaluable network of collaborations and worldwide recognition and opportunities, along with a spirit of unbridled scientific curiosity. The combination with the large scale genetic analyses conducted at CTG and the broader embedding in neuroscience and biology at the CNCR bears exciting future promises.

 

The high-resolution multi-omic atlas of chromatin accessibility and gene expression during the first-trimester of the developing human brain includes more than 100,000 cell-type- and region-specific developmental accessible chromatin regions, as well as inferred candidate cis-regulatory elements and their predicted regulatory effects. The resource allows for example linking transcription factors to putative enhancers, and enhancers to their target genes. In addition, this resource enables the interpretation of genetic associations with disease.

Marijn Schipper, PhD student at CNCR-CTG, investigated whether the parts of DNA that contain open chromatin in specific types of cells during early embryonic development overlap with genetic variants that have been identified previously in genomewide association studies for psychiatric disorders. We found that the patterns of open chromatin in the DNA in specific types of cells during development coincide with stretches of DNA that are also linked to ADHD, anorexia, autism spectrum disorders, depression, insomnia and schizophrenia. The strongest association was found for depression: genetic variants that have previously been linked to depression occur particularly frequently in stretches of DNA that are mainly active during early embryonic development in the GABAergic neurons in the midbrain. This link with the midbrain is novel, and offers new research directions with a specific focus on the midbrain for understanding the hereditary component of depression.

The paper can be found here: https://www.nature.com/articles/s41586-024-07234-1

News article VU website.

 

This study explains at the molecular level why synapses are stronger and depress faster in the absence of tomosyns. The research was mainly performed by Marieke Meijer (Amsterdam UMC), Miriam Öttl (Vrije Universiteit) and Jie Yang (Yale School of Medicine), among others, who combined synapse physiology on a conditional mouse model of tomosyn deficiency with single-molecule force measurements by the Yongli Zhang lab. Our data reveal that tomosyns produce a new intermediate state in SNARE assembly which drastically reduces the probability that synaptic vesicles fuse.

These findings offer a new explanation for the functional heterogeneity of synaptic vesicles (‘primed’ vs ‘superprimed’). By limiting the amount of synaptic vesicles that reside in a highly fusogenic state, tomosyns equalize neurotransmission during activity. This study also advances our understanding on how synapse function can be regulated by targeting the molecular machinery that releases neurotransmitters.

The paper can be found here: https://rdcu.be/dCvS8

Image credit: ‘fragment of vesicles’ by Rini Brakkee

Pathogenic variants in STXBP1/Munc18-1 cause severe encephalopathies that are among the most common in genetic neurodevelopmental disorders. Different molecular disease mechanisms have been proposed and pathogenicity prediction is limited. The new study led by Annemiek van Berkel (FGA), Timon André and Gurdeep Singh (both University of Heidelberg) aimed to define a generalized disease concept for STXBP1-related disorders and improve prediction.

A cohort of 11 disease-associated and five neutral variants (detected in healthy individuals) was tested in three cell-free assays, and in heterologous cells and primary neurons. A machine learning algorithm (PRESR) that uses both sequence- and 3D structure-based features was developed to improve pathogenicity prediction using 231 known disease-associated variants and comparison to our experimental data.

The researchers found that disease-associated, but none of the neutral variants produced reduced protein levels. Cell-free assays demonstrated directly that disease-associated variants have reduced thermostability, with most variants denaturing around body temperature. In addition, most disease-associated variants impaired SNARE- mediated membrane fusion in a reconstituted assay. Moreover, PRESR outperformed existing tools substantially: Matthews correlation coefficient = 0.71 versus <0.55.

Taken together, this study establishes intrinsic protein instability as the generalizable, primary cause for STXBP1-related disorders and shows that protein-specific ortholog and 3D information improves disease prediction. PRESR is a publicly available diagnostic tool:

The paper is available here.

The prediction tool is available here: PRESR.russelllab.org

One gene can influence multiple characteristics of an organism. This phenomenon is called pleiotropy. Tissink and her colleagues from Vrije Universiteit Amsterdam and the University of Oslo investigated the extent to which pleiotropy occurs for several characteristics of the brain. This concerns, for example, structure, function and tissue composition. Discovering genes that contribute to different aspects of the brain can provide insight into brain diseases. For example, if someone has Alzheimer’s, this is not only reflected in the structure of the brain, but also in the functional connections between the brain areas.

New genes
The researchers found that pleiotropy is common. About half of the genes found influence two or three features of the brain. The structure, function and tissue composition of the brain are measured with three different MRI scans: structural, functional, and diffusion MRI. Pleiotropy is widespread across features measured with these three types of MRI scans. Researchers can use this information intelligently. By combining the MRI scans in one genetic analysis, they discovered a significant number of new genes.

Risk model
One potential application already emerged in the research. The scientists used the results in a genetic risk model for brain diseases. “Unfortunately, the predictive value of these models is currently not good enough to use in practice,” says Tissink. “But we did see that this model becomes better at distinguishing patients with bipolar disorder or ADHD from people who do not.”

Donating DNA
Until a few years ago, it would not have been possible to discover these genes with a combination of three different MRI scans and DNA profiles. But because 40,000 people in the United Kingdom donated their DNA and had MRI scans made, this is now possible. It is expected that 100,000 brain scans and DNA profiles will become available for scientific research in the future.

Elleke Tissink worked at the department of Complex Trait Genetics (CNCR) and received her PhD from Vrije Universiteit Amsterdam in September 2023. The research on which the article in Nature Communications is based forms part of her dissertation.

Their project primarily investigates the contrast of normative brain aging trajectories between humans and macaques. Despite apparent similarities in developmental and aging stages between human and macaques, certain disorders like schizophrenia and Alzheimer’s disease seem to be uniquely human. They will analyze neuroimaging data from over 600 macaques and around 5,000 humans to identify key differences in aging patterns and their relation to brain disorders. Their goal is to uncover the aspects of brain aging that may contribute to human vulnerability to these conditions through a cross-species study approach.

With this grant support, she will explore how to enhance candidate gene targets selection by integrating quantitative trait loci (QTLs) and genome-wide association studies (GWAS) data.

Background: Despite the success of GWAS in identifying thousands of genetic variants associated with complex traits, we are still not closer to the quest of narrowing down the targets for therapeutics design. One issue is that an association at the gene level is not enough evidence for the gene to actually cause disease because transcription and/or translation might not be affected. To help pinpoint candidate genes, QTL mapping is used to narrow down GWAS variants that are associated with expression, methylation, or protein levels. With this grant support, Tanya aims to build a web-platform in order to aggregate available QTLs data and to implement state-of-the-art methods for integrating QTLs and GWAS. While this work focuses on QTLs, it will be a foundation for integrating multiple levels of omics data in the future.