Featured articles

Theses

Postdoctoral position in medicinal chemistry for drug discovery in death receptor signaling

We are seeking a talented and enthusiastic researcher with expertise in medicinal chemistry and chemical biology to advance drug discovery efforts and investigations on death receptor signaling and physiology in cancer and neuronal cells. The research entails medicinal chemistry studies on small molecules targeting the p75NTR death receptor identified in our ongoing screens, with the objective to improve the pharmacokinetic and biological properties of chemical leads. Please see Goh et al. (2018) Cell Chemical Biology 25, 1485–1494 for a representative publication of this work.

Candidates will be accepted at the postdoctoral level with a PhD awarded within the last 3 years. Strong and documented expertise in medicinal chemistry and chemical biology is a requirement for consideration. The successful candidate is expected to be sufficiently independent to formulate questions, design experiments and perform research. Excellent command of the English language is reuqired.

Applications, including CV (no diploma copies needed at this time please), list of publications and statement of research interests should be sent vey email to Prof. Carlos Ibanez (carlos [dot] ibanez [at] ki [dot] se) and through the job web page of Karolinska Institute. Applicants should arrange to have at least two confidential letters of reference sent independently by referees to this email address. Funding is available for an initial period of 3 to 4 years.

Deadline for application is 20 September 2019.

Open Postdoctoral Position: Molecular / Cellular Neurobiologists

We are seeking talented and enthusiastic researchers with expertise in molecular and cellular neuroscience to advance investigations on the functions and mechanisms of growth factor receptor signaling and physiology in the nervous system. The research entails studies of different receptor systems in neuronal and nervous system function using molecular methods, cell culture models and mutant mice carrying specific mutations in these receptors.

Candidates will be accepted at the postdoctoral level with a PhD awarded preferably within the last 3 years. Strong and documented expertise in molecular, cellular and histological methods of analysis as applied to studies of mouse models in the area of neuroscience is an absolute requirement for consideration. Successful applicants shall be well versed in mouse brain neuroanatomy and physiology. Expertise in analysis of mouse behavior will be an additional advantage. The successful candidate is expected to be sufficiently independent to formulate questions, design experiments and perform research. For more information and publications, please look HERE in our lab website.

Applications, including CV, list of publications and statement of research interests should be sent through the job web page of Karolinska Institute: Applicants should arrange to have at least two confidential letters of reference sent independently by referees to that email address.

Deadline for application is 15 September 2019.

New postdoc fellow joins KI group to develop medicinal chemistry work on candidate compounds

Michael Saleeb obtained a PhD in Organic Chemistry at Umeå University in Sweden in September 2018, under the direction of Prof. Mikael Elofsson. His PhD thesis was focused on the identification of novel antibacterial compounds against Chlamydia trachomatis & Pseudomonas aeruginosa infections. During his PhD, Michael developed expertise in chemical synthesis including C-C and C-X metal-catalyzed cross coupling, C-H insertion reactions, various heterocyclic and polyphenol syntheses. Michael  joins our KI team to develop medicinal chemistry approaches to modify and improve on candidate small molecules capable of modulating the activities of various receptors, including our recently discovered compounds targeting p75NTR, based on our article in Cell Chemical Biology.  

New postdoc fellow joins KI group to identify small molecules targeting p75NTR

Qiang Zhang obtained his  PhD at the Karolinska Institute in 2018, under the direction of Prof. Klas Wiman. His PhD thesis was entitled “Understanding p53 structure and targeting mutant p53 for improved cancer therapy”. Qiang joins our KI team to work on the identification of small molecules capable of modulating the activities of the p75 neurotrophic receptor p75NTR, based on the platform described in our recent article in Cell Chemical Biology.  

Change of Department affiliation (again)

Carlos Ibanez’s team returns to the Department of Neuroscience after 21 months under the administration of CMB. We are happy to be back, and hope to relocate to new space within Biomedicum later in the year.

New paper reports unexpected convergence of TDP-43 and BDNF signaling hubs in regulation of synaptic plasticity, learning and memory

In this new paper, we report that abnormal TDP‐43 function culminate in impaired secretion of the neurotrophin BDNF, whose restoration is sufficient to rescue major disease phenotypes caused by aberrant TDP‐43 activity.

Aberrant function of the RNA‐binding protein TDP‐43 has been causally linked to multiple neurodegenerative diseases. Due to its large number of targets, the mechanisms through which TDP‐43 malfunction cause disease are unclear. Here, we report that knockdown, aggregation, or disease‐associated mutation of TDP‐43 all impair intracellular sorting and activity‐dependent secretion of the neurotrophin brain‐derived neurotrophic factor (BDNF) through altered splicing of the trafficking receptor Sortilin. Adult mice lacking TDP‐43 specifically in hippocampal CA1 show memory impairment and synaptic plasticity defects that can be rescued by restoring Sortilin splicing or extracellular BDNF. Human neurons derived from patient iPSCs carrying mutated TDP‐43 also show altered Sortilin splicing and reduced levels of activity‐dependent BDNF secretion, which can be restored by correcting the mutation. We propose that major disease phenotypes caused by aberrant TDP‐43 activity may be explained by the abnormal function of a handful of critical proteins, such as BDNF.

The paper has just been published in The EMBO Journal.

Read the full paper HERE.

New postdoc fellow joins KI group

Ana Osorio Oliveira obtained her PhD at the Gladstone Institute, University of California San  Francisco , USA, in 2015, under the direction of Profs. Paul Muchowski and Steven Finkbeiner. She performed postdoctoral studies at Stanford University under the direction of Dr. Xinnan Wang. Ana joins our KI team to work on studies of neurotrophic factor signaling and function in the adult nervous system. 

Singapore media highlights identification of small molecule targeting the transmembrane domain of death receptor p75NTR

The Saturday edition of the The Straits Times publishes today an interview with Carlos Ibanez highlighting the identification a small molecule targeting the transmembrane domain of death receptor p75NTR that induces melanoma cell death and reduces tumor growth (reported in our paper published in Cell Chemical Biology). Read the full article here. Also newspaper Lianhe Zaobao (Chinese Daily) carried a story (in Chinese) on the discovery.

Special award from Cancerfonden to Carlos Ibanez lab for work on small molecules targeting p75NTR in cancer

Cancerfonden, the largest research funding charity organization in Sweden, today decided to award a special grant to Carlos Ibanez lab for drug discovery efforts targeting the p75 neurotrophin receptor in melanoma and glioma, based on our pilot study recently published in Cell Chemical Biology.

New paper reports the identification of a small molecule targeting the transmembrane domain of death receptor p75NTR

In this new paper, we have used a novel chemical biology approach to identify a small molecule targeting the transmembrane domain of death receptor p75NTR that induces melanoma cell death and reduces tumor growth

Small molecules offer powerful ways to alter protein function. However, most proteins in the human proteome lack small-molecule probes, including the large class of non-catalytic transmembrane receptors, such as death receptors. We hypothesized that small molecules targeting the interfaces between transmembrane domains (TMDs) in receptor complexes may induce conformational changes that alter receptor function. Applying this concept in a screening assay, we identified a compound targeting the TMD of death receptor p75NTR that induced profound conformational changes and receptor activity. The compound triggered apoptotic cell death dependent on p75NTR and JNK activity in neurons and melanoma cells, and inhibited tumor growth in a melanoma mouse model. Due to their small size and crucial role in receptor activation, TMDs represent attractive targets for small-molecule manipulation of receptor function.

The paper has just been published in Cell Chemical Biology.

Read the full paper HERE.

New paper shows how RIP2 and TRAF6 compete for binding to p75NTR and regulate neuronal cell death

In this new paper, we show how intracellular effectors RIP2 and TRAF6 compete for binding to the p75NTR intracellular domain to regulate cell death of cerebellar granule neurons.

Cerebellar granule neurons (CGNs) undergo programmed cell death during the first postnatal week of mouse development, coincident with sustained expression of the death receptor p75NTR. Although ablation of p75NTR did not affect CGN cell death, deletion of the downstream effector RIP2 significantly increased CGN apoptosis, resulting in reduced adult CGN number and impaired behaviors associated with cerebellar function. Remarkably, CGN death was restored to basal levels when p75NTR is deleted in RIP2-deficient mice. We found that RIP2 gates the signaling output of p75NTR by competing with TRAF6 for binding to the receptor intracellular domain. In CGNs lacking RIP2, more TRAF6 was associated with p75NTR, leading to increased JNK-dependent apoptosis. In agreement with this, pharmacological inhibition or genetic ablation of TRAF6 restored cell death levels in CGNs lacking RIP2. These results revealed an unexpected mechanism controlling CGN number and highlight how competitive interactions govern the logic of death receptor function.

The paper has just been published in Cell Reports.

Read the full paper HERE.

New paper reveals cell-autonomous role of GFRα1 in the development of olfactory bulb GABAergic interneurons

In this new paper, we show how the GDNF receptor GFRα1 functions cell-autonomously in subpopulations of olfactory bulb interneuron precursors to regulate their generation and allocation in the mammalian olfactory bulb.

GFRα1, a receptor for glial cell line-derived neurotrophic factor (GDNF), is critical for the development of the main olfactory system. The olfactory bulb (OB) of Gfra1 knockout mice showed significant reductions in the number of olfactory sensory neurons, mitral and tufted cells, as well as all major classes of OB GABAergic interneurons. However, the latter did not express significant levels of GFRα1, leaving the mechanism of action of GFRα1 in OB interneuron development unexplained. We have found that GFRα1 is highly expressed in the precursor cells that give rise to all major classes of OB interneurons, but is downregulated as these neurons mature. Conditional ablation of GFRα1 in embryonic GABAergic cells recapitulated the cell losses observed in global Gfra1 knockouts at birth. GFRα1 was also required for the sustained generation and allocation of OB interneurons in adulthood. Conditional loss of GFRα1 altered the migratory behaviour of neuroblasts along the rostral migratory stream (RMS) as well as RMS glial tunnel formation. Together, these data indicate that GFRα1 functions cell-autonomously in subpopulations of OB interneuron precursors to regulate their generation and allocation in the mammalian OB.

The paper has just been published in Biology Open.

Read the full paper HERE.

Carlos Ibanez lab moves to the new Biomedicum building

Today is the big day. After many years of planning and construction, all the preclinical departments of Karolinska Institute move into a huge, brand-new building called BIOMEDICUM. Very handsome on the inside, less so on the outside. We are just hoping for a smooth transition.

Carlos Ibanez presents the Nobel Prize in Physiology or Medicine 2017

Presentation Speech by Professor Carlos Ibáñez, Member of the Nobel Assembly at the Karolinska Institute, Member of the Nobel Committee for Physiology or Medicine, at the award ceremony of the Nobel Prize, 10 December 2017.

New postdoc fellow joins KI group to study roles of p75NTR signaling in neuron survival and differentiation

Shounak Baksi obtained his PhD at the University of Calcutta, India, in September 2009. His thesis work focused on studies of alterations in Growth Factor Receptor Protein Binding Protein 2 (Grb2) signaling in Huntington’s disease cell model. His postdoctoral studies in Case Western Reserve University, Cleveland, OH, under the direction of Dr. Neena Singh,  focused on the role of Parkinson’s disease protein alpha synuclein in retinal and brain iron homeostasis. Shounak established the role of alpha synuclein in the process of transferrin receptor endocytosis. Shounak joins the KI team to pursue studies of p75 signaling mutant mice.

Change of Department affiliation

Carlos Ibanez’s team is now under the Department of Cell and Molecular Biology (CMB) of Karolinska Institute. Although the group was since 1996 under the Department of Neuroscience, its laboratories were already located at CMB space since 2004. This administrative change completes the integration of the Ibanez team in the CMB organization, in preparation for the big move to the new Biomedicum building next year.

New paper reveals how GDNF controls survival of molecular layer interneurons in the cerebellum

In this new paper, we show how the GDNF regulates survival of molecular layer interneurons in the cerebellum to control normal cerebellar motor learning. The paper has just been published in Cell Reports.

The role of neurotrophic factors as endogenous survival proteins for brain neurons remains contentious. In the cerebellum, the signals controlling survival of molecular layer interneurons (MLIs) are unknown, and direct evidence for the requirement of a full complement of MLIs for normal cerebellar function and motor learning has been lacking. Here, we show that Purkinje cells (PCs), the target of MLIs, express the neurotrophic factor GDNF during MLI development and survival of MLIs depends on GDNF receptors GFRα1 and RET. Conditional mutant mice lacking either receptor lose a quarter of their MLIs, resulting in compromised synaptic inhibition of PCs, increased PC firing frequency, and abnormal acquisition of eyeblink conditioning and vestibulo-ocular reflex performance, but not overall motor activity or coordination. These results identify an endogenous survival mechanism for MLIs and reveal the unexpected vulnerability and selective requirement of MLIs in the control of cerebellar-dependent motor learning.

Read the full paper HERE.

Open Position: Cellular Electrophysiologist

UPDATE 2017-05-29: Position still open. 

We are seeking a talented and enthusiastic researcher with expertise in cellular electrophysiology to advance investigations on the functions and mechanisms of neurotrophic signaling networks in the adult nervous system. The research entails functional assessment of neuronal circuits in the brains of mutant mice lacking different neurotrophic factor receptors in specific subpopulations of neurons.

Candidates will be accepted at the postdoctoral level with a PhD awarded preferably within the last 5 years. Strong and documented expertise in electrophysiological methods as applied to studies of the rodent central nervous system, such as electrophysiological recordings from brain slices, is a requirement for consideration. Experience on calcium imaging would be an advantage.

The successful candidate is expected to be sufficiently independent to set up electrophysiological methods at our laboratory, including supervision of purchase, installation and maintenance of the necessary equipment.

Applications, including CV, list of publications and statement of future interests should be sent to Prof. Carlos Ibanez carlos [dot] ibanez [at] ki [dot] se. Applicants should arrange to have at least two confidential letters of reference sent independently by referees to this email address.

Funding is available for an initial period of 3 to 4 years, starting any time during 2017.

Open Postdoctoral Position: Molecular / Cellular Neurobiologists

UPDATE 2017-05-29: The position has been filled. 

We are seeking a talented and enthusiastic researcher with expertise in molecular and cellular neurobiology to advance investigations on the functions and mechanisms of neurotrophic signaling in the nervous system. The research entails studies of death receptor signaling pathways in cell culture models as well as phenotypic characterisation of mutant mice carrying specific mutations in neurotrophic factor receptors. Please refer to our recent list of publications in this area HERE.

Candidates will be accepted at the postdoctoral level (PhD awarded within the last 5 years). Strong and documented expertise in cellular, molecular and histological methods as applied to studies of the rodent nervous system is a requirement for consideration. Experience with genetically modified mice is highly desirable. The successful candidate is expected to be sufficiently independent to formulate questions, design experiments and perform research.

Our group belongs to a network of laboratories dedicated to different aspects of neuroscience research and provides a strong environment for scientific growth and career development.

Applications, including CV, list of publications and statement of future interests should be sent to Prof. Carlos Ibanez carlos [dot] ibanez [at] ki [dot] se. Applicants should arrange to have at least two confidential letters of reference sent independently by referees to this email address.

Funding is available for an initial period of 3 years, starting any time during 2017.

Deadline for application is March 7, 2017.

Joint retreat of KI and NUS labs in Singapore

Fellows from the KI lab flew to Singapore for a 2 day retreat with the NUS group on 16th and 17th of January 2017. After 4 years of joint lab meetings over Skype, fellows of both groups enjoyed an opportunity to discuss common projects and ideas face to face. We were joined by the NUS and UCSD groups of Prof. Ed Koo and had joint plenary and also parallel sessions, as well as group building activities, as shown in the photo below.

 

New paper shows novel function of the GFRα1 receptor

In this new paper, we show how the GFRα1 receptor regulates Purkinje cell migration independently of GDNF or RET, by limiting the function of NCAM. The paper has just been published in Cell Reports.

During embryonic development of the cerebellum, Purkinje cells (PCs) migrate away from the ventricular zone to form the PC plate. The mechanisms that regulate PC migration are incompletely understood. Here, we report that the neurotrophic receptor GFRα1 is transiently expressed in developing PCs and loss of GFRα1 delays PC migration. Neither GDNF nor RET, the canonical GFRα1 ligand and co-receptor, respectively, contribute to this process. Instead, we found that the neural cell adhesion molecule NCAM is co-expressed and directly interacts with GFRα1 in embryonic PCs. Genetic reduction of NCAM expression enhances wild-type PC migration and restores migration in Gfra1 mutants, indicating that NCAM restricts PC migration in the embryonic cerebellum. In vitro experiments indicated that GFRα1 can function both in cis and trans to counteract NCAM and promote PC migration. Collectively, our studies show that GFRα1 contributes to PC migration by limiting NCAM function.

Read the full paper HERE.

New paper shows how thalamo-cortical axons regulate the radial dispersion of neocortical GABAergic interneurons

In our latest paper, we show how thalamo-cortical axons regulate the radial dispersion of neocortical GABAergic interneurons. The paper has just been published in eLife.

Neocortical GABAergic interneuron migration and thalamo-cortical axon (TCA) pathfinding follow similar trajectories and timing, suggesting they may be interdependent. The mechanisms that regulate the radial dispersion of neocortical interneurons are incompletely understood. In this new study we report that disruption of TCA innervation, or TCA-derived glutamate, affected the laminar distribution of GABAergic interneurons in mouse neocortex, resulting in abnormal accumulation in deep layers of interneurons that failed to switch from tangential to radial orientation. Expression of the KCC2 cotransporter was elevated in interneurons of denervated cortex, and KCC2 deletion restored normal interneuron lamination in the absence of TCAs. Disruption of interneuron NMDA receptors or pharmacological inhibition of calpain also led to increased KCC2 expression and defective radial dispersion of interneurons. Thus, although TCAs are not required to guide the tangential migration of GABAergic interneurons, they provide crucial signals that restrict interneuron KCC2 levels, allowing coordinated neocortical invasion of TCAs and interneurons.

Read the full paper HERE. (Supplemental information 31.6MB)

Swedish Research Council awards new research grant to Carlos Ibanez Lab

The Swedish Research Council (Vetenskapsrådet) has awarded a new grant to our KI group for work on neurotrophic signaling in the adult nervous system and its importance for neuropsychiatric disorders. Tack för förtroendet!

Carlos Ibanez named Weston Visiting Professor at the Weizmann Institute of Science

The Weizmann Institute in Israel has named Carlos Ibanez Weston Visiting Professor in the Faculty of Biochemistry, Department of Biomolecular Sciences for 3 years, starting October 2016 to conduct educational and research activities.

New lab technician joins KI group to help with histology and imaging

Wei Wang has a BSc in Public Health from Medical College of Southeast University, Nanjing, China, and a MSc in Environmental Toxicology from Shanghai Medical College, Fudan University, Shanghai, China. She has worked as Assistant Researcher at the Shanghai Institute of Applied Physics, Shanghai Institutes for Biological Sciences and the University of Gothenburg in Sweden. She joins our group to assist with histological methods and imaging of tissue samples from our mouse models.

New paper demonstrates requirement of p75NTR death domain and transmembrane cysteine for neuronal death in the CNS

In our latest paper, we show how dimers of the p75NTR neurotrophin receptor are indipensable for p75NTR-mediated cell death in the central nervous system. The paper has just been published in the Journal of Neuroscience.

The oligomeric state and activation mechanism that enable p75 NTR to mediate these effects have recently been called into question. In this new study, we have investigated mutant mice lacking the p75NTR death domain (DD) or a highly conserved transmembrane (TM) cysteine residue (Cys 259) implicated in receptor dimerization and activation. Neuronal death induced by proneurotrophins or epileptic seizures was assessed and compared with responses in p75NTR knock-out mice and wild-type animals. Proneurotrophins induced apoptosis of cultured hippocampal and cortical neurons from wild-type mice, but mutant neurons lacking p75NTR, only the p75NTR DD, or just Cys259 were all equally resistant to proneurotrophin-induced neuronal death. Homo-FRET anisotropy experiments demonstrated that both NGF and proNGF induce conformational changes in p75 NTR that are dependent on the TM cysteine. In vivo, neuronal death induced by pilocarpine-mediated seizures was significantly reduced in the hippocampus and somatosensory, piriform, and entorhinal cortices of all three strains of p75 NTR mutant mice. Interestingly, the levels of protection observed in mice lacking the DD or only Cys 259 were identical to those of p75 NTR knock-out mice even though the Cys 259 mutant differed from the wild-type receptor in only one amino acid residue. We conclude that, both in vitro and in vivo, neuronal death induced by p75NTR requires the DD and TM Cys259, supporting the physiological relevance of DD signaling by disulfide-linked dimers of p75NTR in the CNS.

Read the full paper HERE.

Open position: Laboratory technician - Histology

UPDATE 2016-05-25: The position has been filled. 

We are seeking a laboratory technician to help us with histological studies of our lines of mutant mice. The candidates should have documented expertise in histological techniques, including tissue sectioning, immunohistochemistry and microscopy. Experience in histological analysis of nervous tissue is preferred. This is a project employment for a period of up to 2 years.

Application, including CV and reference names of two latest project supervisors should be sent to Prof. Carlos Ibanez carlos [dot] ibanez [at] ki [dot] se

Deadline for application is 29th April, 2016

New review article published: Biology of GDNF and its receptors — Relevance for disorders of the central nervous system

A targeted effort to identify novel neurotrophic factors for midbrain dopaminergic neurons resulted in the isolation of GDNF (glial cell line-derived neurotrophic factor) from the supernatant of a rat glial cell line in 1993. Over two decades and 1200 papers later, the GDNF ligand family and their different receptor systems are now recognized as one of the major neurotrophic networks in the nervous system, important for the devel- opment, maintenance and function of a variety of neurons and glial cells. The many ways in which the four mem- bers of the GDNF ligand family can signal and function allow these factors to take part in the control of multiple types of processes, from neuronal survival to axon guidance and synapse formation in the developing nervous system, to synaptic function and regenerative responses in the adult. In this review, recently published in Neurobiology Of Disease, basic aspects of GDNF signaling mechanisms and receptor systems are first summarized followed by a review of current knowledge on the physiology of GDNF activities in the central nervous system, with an eye to its relevance for neurodegenerative and neuropsychiatric diseases. Read the full paper HERE.

New paper describes first structures of protein complexes of the p75NTR death domain

Our latest paper describes new NMR structures of the death domain in complex with downstream interactions RhoGDI and RIP2 as well as the death domain dimer. These are the first structural insights into p75NTR signaling and reveal many surprises for the death domain superfamily. The paper is now available online at eLife

Death domains (DDs) mediate assembly of oligomeric complexes for activation of downstream signaling pathways through incompletely understood mechanisms. We report structures of complexes formed by the DD of p75 neurotrophin receptor (p75NTR) with RhoGDI, for activation of the RhoA pathway, with caspase recruitment domain (CARD) of RIP2 kinase, for activation of the NF-kB pathway, and with itself, revealing how DD dimerization controls access of intracellular effectors to the receptor. RIP2 CARD and RhoGDI bind to p75NTR DD at partially overlapping epitopes with over 100-fold difference in affinity, revealing the mechanism by which RIP2 recruitment displaces RhoGDI upon ligand binding. The p75NTR DD forms non-covalent, low-affinity symmetric dimers in solution. The dimer interface overlaps with RIP2 CARD but not RhoGDI binding sites, supporting a model of receptor activation triggered by separation of DDs. These structures reveal how competitive protein-protein interactions orchestrate the hierarchical activation of downstream pathways in non-catalytic receptors.

Cancerfonden awards new research grant to Carlos Ibanez Lab

The Swedish Cancer Society (Cancerfonden) has awarded a new grant to our KI group for work on ALK7, p75 and GDNF signalling and biology. Tack för förtroendet!