The mechanisms driving neurodegeneration in Parkinson’s remain incompletely understood, and disease-modifying therapies are still lacking. Although genetic forms of Parkinson’s are rare, they have provided crucial insights into disease mechanisms.
This project will be led by Dr. Ana Carreras Mascaro, who will investigate how specific genetic variants in Parkinson’s disease contribute to neurodegeneration in a physiologically relevant context. Building on Neurospector’s optimized human dopaminergic neuron cultures, she will develop new cell models to study early-onset, genetically driven Parkinson’s.
This research aims to uncover novel pathways involved in neurodegeneration and ultimately support the development of future therapeutic strategies.
Dr. Sanne Beerens (Memory Circuits team) will investigate how different intensities of aversive experiences alter synaptic properties of engram neurons in the prefrontal cortex. This could explain why traumatic memories in PTSD are so persistent while other fear memories fade.
Dr. Janina Kupke (Memory Circuits & Molecular Engram teams) will study whether DNA methylation, a lasting chemical mark on DNA, helps engram neurons maintain stable synaptic connections over time. Using advanced genetic tools and synapse-specific proteomics, she will map the protein landscape of engram synapses to reveal the molecular signatures that keep memories alive.
By revealing how engram neurons store and adapt memories, these projects aim to uncover new targets that may be new entry points for treatment of memory loss in Alzheimer’s disease, age-related cognitive decline, and the persistence of traumatic memories in PTSD.
Stressful experiences are generally remembered well, but such memories are often less precise, which results in memory generalization (recall of the stressful event when this is not relevant). This effect is mediated by stress-hormones. We will investigate how stress-hormones enhance memory generalization by studying the properties of the specific cells in the brain that store a memory, so-called engram cells. For this, we examine their specific cellular properties, their connections, and how we can reverse the effects of stress hormones to prevent memory generalization.
We will hire two PhD candidates for the project. If you are interested, please apply here.
You can only apply through this website. Please do not send applications directly to Dr. Krugers and/or Dr. van den Oever.
Neurons secrete chemical signal by two main principles: neurotransmitter release from synaptic vesicles (SVs) and neuropeptides from dense-core vesicles (DCVs). The presynaptic proteins RIM and MUNC13 play key roles in both pathways. However, it was still unclear how DCVs are targeted to release sites and whether RIM and MUNC13 are involved in this process. In the current study, Fiona Murphy and team show that three membrane-binding domains in RIM and MUNC13 regulate neuropeptide secretion and do so in a manner that is different from the way these same protein regulate neurotransmitter release.
Using neuropeptide secretion assays with single-vesicle resolution and peptidomics analysis of endogenous neuropeptide release in MUNC13/RIM null mutant neurons, the authors demonstrate that MUNC13 is essential for neuropeptide secretion. The N-terminus of RIM prevents MUNC13 degradation via the proteasome, and inhibiting proteasomal degradation partially restored neuropeptide secretion in RIM’s absence. RIM and MUNC13 both contain a C2 domain, a protein domain known to bind/recruit specific positively charged phospholipids in the plasma membrane (PIP2) that are known to be important for the membrane fusion reaction. The RIM C2 domain and the MUNC13 C1-C2B polybasic face are both essential for neurotransmitter release. However, the authors show that the two domains are redundant for neuropeptide secretion. In contrast, the lipid-binding MUNC13 C2C domain is essential.
This study shows that RIM and MUNC13 synergistically regulate neuropeptide secretion through membrane interactions and reveal new mechanistic differences between SV and DCV secretion principles.
The study was published in The Journal of Cell Biology and be found here:
This prestigious award is bestowed upon individuals whose groundbreaking scientific contributions have significantly advanced our understanding of STXBP1-related disorders. Prof. Verhage’s long-standing dedication to translational research has been instrumental in uncovering critical disease mechanisms in SNAREopathies, particularly STXBP1. His tireless efforts have not only expanded our scientific knowledge but also paved the way for potential new therapies, offering hope to countless families affected by these conditions.
We are incredibly proud to have Prof. Verhage’s expertise and leadership within the STXBP1 community. His work continues to inspire progress and innovation in the field of rare disease research.
While Prof. Verhage was unable to attend this year’s STXBP1 Summit + Family Meeting in Colorado organized by the STBPX1 Foundation, they celebrated his achievements with a special award ceremony. A short acceptance video from Prof. Verhage was shared during the event, which allowed the attendees to honor his remarkable accomplishments and contributions to the field.
Please join us in congratulating Prof. Verhage on this well-deserved recognition. His passion and dedication to advancing the understanding of STXBP1-related disorders have made a profound impact on both the scientific community and families worldwide.
Acceptance video of Innovative Research Award by Verhage lab.
The Locus Coeruleus (LC) is the brain’s main source of noradrenaline (NA) and a key “first responder” to stressful events. In challenging situations (e.g., fearful or anxiogenic environments), the LC-NA system drives critical functions such as arousal, attention, and decision-making, triggering rapid “fight-or-flight” responses. When this system becomes overactive, it can lead to heightened stress reactivity and contribute to conditions like anxiety disorders.
The researchers (Neuromodulation of Cognition) hypothesized that peptidergic neuromodulation might act as a natural brake on LC activity, thereby keeping our stress response in check. To investigate this, they used a combination of advanced techniques – genetic labelling, viral tracing, electrophysiology, imaging of peptide release dynamics, and in vivo chemogenetic and pharmacological interventions. They discovered a previously unknown group of Neuropeptide Y (NPY)-expressing neurons that surround the LC. These peri-LC NPY cells form inhibitory connections with LC neurons, dampening their activity. When the team activated or silenced these cells, they saw corresponding changes in anxiety-like behaviours, showing that this local NPY system plays a direct role in modulating the stress response.
Collectively, this work reveals a new circuit-level mechanism for how the brain responds to adversity, highlighting the importance of endogenous peptidergic signalling in maintaining adaptive responses to stress.
The ADORE Centre (Amsterdam Oncology and Neuroscience Research) is a pioneering facility, the first of its kind to establish a structural collaboration between cancer and neuroscience experts. By integrating the fields of neurology and oncology, ADORE fosters interdisciplinary partnerships and promotes the exchange of knowledge, accelerating the development of innovative healthcare solutions for a broad range of patients.
At the heart of ADORE’s research is the TRANSVISION project, which employs ultra-sensitive technologies to study cell-to-cell communication at the level of individual cells. Researchers are particularly focused on how tumor cells and brain cells interact, aiming to pinpoint the proteins involved in these exchanges. This deeper understanding could unlock new, precisely targeted treatment strategies.
“The better we understand how cells ‘talk’ to each other, the more precisely we can intervene and develop new medications,” said Guus Smit, Director of Neuroscience Research at ADORE.
During the opening ceremony, several researchers from the CNCR had the opportunity to engage with Queen Máxima. Among them was postdoctoral researcher Ana Carreras Mascaro from the Neurospector team, who gave the Queen a glimpse of our cultured human neurons through a microscope. Senior researchers Femke Feringa and Rik van der Kant also spoke with Her Majesty, sharing insights from their groundbreaking work on Alzheimer’s disease.
Photography by Mark van den Brink, Amsterdam UMC
Promising step
Rik van der Kant discovered that cholesterol buildup in brain cells of Alzheimer’s patients directly leads to an accumulation of the toxic proteins Tau and Amyloid. He also found that Efavirenz might be suitable for reversing this buildup. Dr. Jort Vijverberg, Neurologist at the Alzheimer Center is also hopeful about the trial “We are very curious to see how this medication will work in Alzheimer’s patients, I consider it a promising step in the right direction.”
Participants needed
The trial is still looking for participants. In total, forty patients are needed to take part in the three-month clinical trial in Amsterdam. Participants can take part if they have been diagnosed with early-stage Alzheimer’s disease, are between 50 and 75 years old, and have a family member or caregiver who can accompany them to the research center visits and answer questions about their health and daily functioning. If participants are unsure whether they want to or are able to take part, they can always register without obligation. Their eligibility to participate will be assessed at a later stage.”
For more information, visit Efavirenz – Brain Research Center
Schizophrenia and height are both associated with, among other things, hormonal imbalance, brain size, socioeconomic status, infections and nutrition. Neuroscientist Cato Romero and his colleagues therefore investigated which biological processes schizophrenia and height have in common, to see whether this overlap can provide more information about how schizophrenia develops. The study was published in Biological Psychiatry
The study by Romero et al. used data from large datasets of hundreds of thousands of participants to compare the genetic variation associated with schizophrenia with the genetic variation associated with height. By analyzing DNA variation, they identified genetic markers that relate to both.
Thyroid hormones and immune response
The researchers discovered 142 genes that were linked to both schizophrenia and height. The shared genes showed high expression in the pituitary gland, a small organ that secretes several essential hormones. Within the pituitary, one type of cell, the thyrotrope, stood out in the findings: thyrotropes produce thyroid-stimulating hormone, which regulates the level of thyroid hormones in the body.
In addition, many of the shared genes are involved in the immune response. A large number of genes are active in white blood cells, which help the body fight infection. A link between increased inflammation and schizophrenia has previously been found. It is possible be that the body spends more energy on recovering from infections and therefore less on growth.
Diversity in genetic studies
A caveat to the study is that the evidence for these findings was less robust in datasets from non-European people. This is partly due to the fact that non-European datasets are currently still significantly smaller. According to Romero, there is therefore a need to increase diversity in genetic studies.
For now, this new knowledge about shared genetic mechanisms inspires further research into the exact relation between schizophrenia on the one hand and immune responses and thyroid hormone on the other.
The article can be found here:
https://www.sciencedirect.com/science/article/pii/S1074742725000140?via%3Dihub
In this article, the authors performed closer investigation of so-called engram cells which are thought to harbor the physical representation of memories. While numerous engram cells across the brain are activated during memory formation, only a subset is reactivated during recall. In this project, the authors investigated whether structural synaptic connectivity of these reactivated and non-reactivated engram cells differs in the hippocampus and whether this is dependent on the context valence. To achieve this, a novel analysis pipeline was developed that enables semi-automatic reconstruction of spines and dendrites based on fluorescent labelling of engram cells. The pipeline also integrates multilevel statistical analyses to account for the nested data structure. The authors found that at the level of excitatory CA3 to CA1 engram cells, structural synaptic connectivity of CA1 engram cells is influenced by contextual valence, reactivation status of an engram cell, or a combination thereof. Specifically, parameters related to the number, distribution, and morphology of CA1 engram cell synapses vary based on these factors. These findings give first indications that engram cells follow distinct pathways in structural synaptic connectivity, which may be essential for refining and sustaining engram networks over time.
The analysis pipeline is accessible on GitHub under the following link:
https://github.com/PantheaNemat/structural_dendrite_spine_analysis