A5078507770- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Nerve injury and regeneration
- Metabolism and Genetic Disorders
- Muscle Physiology and Disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA Research and Splicing
- Muscle metabolism and nutrition
- Monoclonal and Polyclonal Antibodies Research
- Peroxisome Proliferator-Activated Receptors
- Adipose Tissue and Metabolism
- Protein Kinase Regulation and GTPase Signaling
- biodegradable polymer synthesis and properties
- Glycosylation and Glycoproteins Research
- Diet and metabolism studies
- Congenital Anomalies and Fetal Surgery
- Neurogenesis and neuroplasticity mechanisms
- RNA modifications and cancer
- Mass Spectrometry Techniques and Applications
- Cancer, Hypoxia, and Metabolism
- Extracellular vesicles in disease
- Prion Diseases and Protein Misfolding
- Lipoproteins and Cardiovascular Health
- Lipid metabolism and disorders
- interferon and immune responses
Karolinska Institutet
2015-2025
Max Planck Institute of Molecular Cell Biology and Genetics
2024-2025
Utrecht University
1986-1988
Grünenthal Group (Germany)
1976
SUMMARY Cytosolic aggregation of the nuclear protein TDP-43 is associated with many neurodegenerative diseases, but triggers for are still debated. Here, we demonstrate that requires a double event. One up-concentration in stress granules beyond threshold, and other oxidative stress. These two events collectively induce intra-condensate demixing, giving rise to dynamic enriched phase within granules, which subsequently transitions into pathological aggregates. Mechanistically, demixing...
Spinal motor axons traverse large distances to innervate target muscles, thus requiring local control of cellular events for proper functioning. To interrogate axon-specific processes we developed Axon-seq, a refined method incorporating microfluidics, RNA sequencing (RNA-seq), and bioinformatic quality control. We show that the axonal transcriptome is distinct from somas contains fewer genes. identified 3,500-5,000 transcripts in mouse human stem cell-derived spinal axons, most which are...
Abstract Neurodegeneràve diseases such as amyotrophic lateral sclerosis (ALS) are oten associated with mutàons in proteins that stress granules. Stress granules condensates formed by liquid-liquid phase separàon which, when aberrant, can lead to altered condensàon behaviours and disease phenotypes. Here, we identified lipoamide, a small molecule which specifically prevents cytoplasmic of granule proteins. Thermal proteome profiling showed lipoamide preferentially stabilises intrinsically...
Neuromuscular junctions are primary pathological targets in the lethal motor neuron diseases spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Synaptic pathology denervation of target muscle fibers has been reported prior to appearance clinical symptoms mouse models both diseases, suggesting that neuromuscular highly vulnerable from very early stages, a key for therapeutic intervention. Here we examined longitudinally three clinically relevant groups ALS SMA order assess...
In amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), lower brainstem motor neurons degenerate, but some neuron subtypes are spared, including oculomotor (OMNs). The mechanisms responsible for this selective degeneration largely unknown, the molecular signatures of resistant vulnerable distinct offer clues to neuronal resilience susceptibility. Here, we demonstrate that healthy OMNs preferentially express Synaptotagmin 13 (SYT13) compared neurons. end-stage ALS patients,...
Endurance exercise promotes skeletal muscle vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. Importantly, the metabolic contractile properties of fiber must be coupled to identity innervating motor neuron (MN). Here, we show that muscle-derived neurturin (NRTN) acts on fibers MNs couple their characteristics. Using a muscle-specific NRTN transgenic mouse (HSA-NRTN) RNA sequencing MN somas, observed retrograde signaling shift toward slow...
Somatic motor neurons are selectively vulnerable in spinal muscular atrophy (SMA), which is caused by a deficiency of the ubiquitously expressed survival neuron protein. However, some groups, including oculomotor and trochlear (ocular), innervate eye muscles, for unknown reasons spared. To reveal mechanisms vulnerability resistance SMA, we investigate transcriptional dynamics discrete neuronal populations using laser capture microdissection coupled with RNA sequencing (LCM-seq). Using gene...
Oculomotor neurons, which regulate eye movement, are resilient to degeneration in the lethal motor neuron disease amyotrophic lateral sclerosis (ALS). It would be highly advantageous if resilience could modeled vitro. Toward this goal, we generated a high proportion of oculomotor neurons from mouse embryonic stem cells through temporal overexpression PHOX2A neuronal progenitors. We demonstrate, using electrophysiology, immunocytochemistry, and RNA sequencing, that vitro-generated bona fide...
ABSTRACT The mesoscale organization of cells is central to cellular physiology and pathology. Cellular condensates often form via biomolecular phase separation, mediated by intrinsically disordered regions (IDRs) represent a key mechanism for organization. TRI-partite Motif (TRIM) family ubiquitin ligases implicated in diverse functions disease, yet the role condensation TRIM remains understudied. Here, we systematically investigate localization 72 proteins, revealing that majority distinct...
Abstract Recent studies in neuron‐glial metabolic coupling have shown that, the CNS, astrocytes and oligodendrocytes support neurons with energy‐rich lactate/pyruvate via monocarboxylate transporters (MCTs). The presence of such PNS, both Schwann cells neurons, has prompted us to question if a similar interaction may be present. Here we describe generation characterization conditional knockout mouse models where MCT1 or MCT4 is specifically deleted (named cKO). We show that cKO mice develop...
Abstract Mutations in FUS and TARDBP cause amyotrophic lateral sclerosis (ALS), but the precise mechanisms of selective motor neuron degeneration remain unresolved. To address if pathomechanisms are shared across mutations related to either gain- or loss-of-function, we performed single-cell RNA sequencing isogenic induced pluripotent stem cell-derived types, harbouring P525L, R495X, M337V knockout. Transcriptional changes were far more pronounced neurons than interneurons. About 20%...
Cytosolic aggregation of the nuclear protein TAR DNA-binding 43 (TDP-43) is associated with many neurodegenerative diseases, but triggers for TDP-43 are still debated. Here, we demonstrate that requires a double event. One up-concentration in stress granules beyond threshold, and other oxidative stress. These two events collectively induce intra-condensate demixing, giving rise to dynamic TDP-43-enriched phase within granules, which subsequently transition into pathological aggregates....
Haemagglutinins which specifically combine with membrane determinants of human blood group A erythrocytes and are distinguishable from any other haemagglutinin specificities display marked sex dependency in C57BL/10 mice. All the sera 80-day-old females exert moderate to strong anti-A activities could be detected only approximately half males same age. Investigations murine tissues revealed that production haemagglutinins is reflected by simultaneous synthesis endogenous receptors ovaries...
Neuronal processes have an RNA composition that is distinct from the cell body.Therefore, to fully understand neuronal biology in health and disease we need study both somas, dendrites axons.Here describe a detailed protocol of newly refined method, Axon-seq, for sequencing axons (and dendrites) grown isolation using single microfluidic devices.We also detail how generate motor neurons mouse human pluripotent stem cells sequencing, but Axon-seq applicable any cell.In are recruited through...
Abstract Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of somatic motor neurons (MNs), which innervate skeletal muscles. However, certain MN groups including ocular MNs that regulate eye movement are relatively resilient to ALS. To reveal mechanisms differential susceptibility, we investigate transcriptional dynamics two vulnerable and populations in SOD1G93A ALS mice. Analysis differentially expressed genes (DEGs) shows each neuron type displays a largely...
Abstract Guinea pig alveolar macrophages were labeled by incubation with either arachidonate or linoleate. Arachidonate phosphatidylcholine (PC), phosphatidylethanolamine (PE) and triglycerides (TG) equally well, each lipid containing about 30% of total cellular radioactivity. In comparison to arachidonate, linoleate was recovered significantly less in PE (7%) more TG (47%). To investigate whether redistributions acyl chains among classes took place, the incubated 1‐acyl‐2‐[1‐ 14...