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Akkuratov, E. E., Sorrell, F., Picton, L. D., Sousa, V. C., Paucar, M., Jans, D., . . . Aperia, A. (2025). ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a dystonia model. Brain, 148(4), 1099-1105
Open this publication in new window or tab >>ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a dystonia model
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2025 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 148, no 4, p. 1099-1105Article in journal (Refereed) Published
Abstract [en]

Mutations in the gene encoding the alpha3 Na+/K+-ATPase isoform (ATP1A3) lead to movement disorders that manifest with dystonia, a common neurological symptom with many different origins, but for which the underlying molecular mechanisms remain poorly understood. We have generated an ATP1A3 mutant mouse that displays motor impairments and a hyperexcitable motor phenotype compatible with dystonia. We show that neurons harbouring this mutation are compromised in their ability to extrude raised levels of intracellular sodium, highlighting a profound deficit in neuronal sodium homeostasis. We show that the spinal motor network in ATP1A3 mutant mice has a reduced responsiveness to activity-dependent rises in intracellular sodium and that this is accompanied by loss of the Na+/K+-ATPase-mediated afterhyperpolarization in motor neurons. Taken together, our data support that the alpha3 Na+/K+-ATPase is important for cellular and spinal motor network homeostasis. These insights suggest that it may be useful to consider ways to compensate for this loss of a critical afterhyperpolarization-dependent control of neuronal excitability when developing future therapies for dystonia.

Place, publisher, year, edition, pages
Oxford University Press (OUP), 2025
Keywords
ATP1A3 gene, motor control, Na+/K+-ATPase, rapid-onset dystonia-parkinsonism, spinal cord
National Category
Neurology Neurosciences Medical Genetics and Genomics
Identifiers
urn:nbn:se:kth:diva-363127 (URN)10.1093/brain/awae373 (DOI)001401984300001 ()39533828 (PubMedID)2-s2.0-105002980978 (Scopus ID)
Note

QC 20250507

Available from: 2025-05-06 Created: 2025-05-06 Last updated: 2025-05-07Bibliographically approved
Kouznetsova, A., Valentiniene, S., Liu, J.-G., Kitajima, T. S., Brismar, H. & Hoog, C. (2024). Aurora B and Aurora C pools at two chromosomal regions collaboratively maintain chromosome alignment and prevent aneuploidy at the second meiotic division in mammalian oocytes. Frontiers in Cell and Developmental Biology, 12, Article ID 1470981.
Open this publication in new window or tab >>Aurora B and Aurora C pools at two chromosomal regions collaboratively maintain chromosome alignment and prevent aneuploidy at the second meiotic division in mammalian oocytes
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2024 (English)In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 12, article id 1470981Article in journal (Refereed) Published
Abstract [en]

Correct chromosome segregation is essential to preserve genetic integrity. The two protein kinases, Aurora B and its meiotic homolog Aurora C, regulate attachments between chromosomal kinetochores and microtubules, thereby contributing to the accuracy of the chromosome segregation process. Here we performed a detailed examination of the localization and activity of Aurora B/C kinases, their partner Incenp and the kinetochore target Hec1, during the second meiotic division in mouse oocytes. We found that a majority of Aurora B and C changed their localization from the outer kinetochore region of chromosomes at prometaphase II to an inner central region localized between sister centromeres at metaphase II. Depletion of the Aurora B/C pool at the inner central region using the haspin kinase inhibitor 5-iodotubercidin resulted in chromosome misalignments at the metaphase II stage. To further understand the role of the Aurora B/C pool at the central region, we examined the behaviour of single chromatids, that lack a central Aurora B/C pool but retain Aurora B/C at the outer kinetochores. We found that kinetochore-microtubule attachments at single chromatids were corrected at both prometaphase II and metaphase II stages, but that single chromatids compared to paired chromatids were more prone to misalignments following treatment of oocytes with the Aurora B/C inhibitory drugs AZD1152 and GSK1070916. We conclude that the Aurora B/C pool at the inner central region stabilizes chromosome alignment during metaphase II arrest, while Aurora B/C localized at the kinetochore assist in re-establishing chromosome positioning at the metaphase plate if alignment is lost. Collaboratively these two pools prevent missegregation and aneuploidy at the second meiotic division in mammalian oocytes.

Place, publisher, year, edition, pages
Frontiers Media SA, 2024
Keywords
Aurora B, Aurora C, meiosis, oocyte, second meiotic division, aneuploidy
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-354790 (URN)10.3389/fcell.2024.1470981 (DOI)001322281400001 ()39355122 (PubMedID)2-s2.0-85205521799 (Scopus ID)
Note

QC 20241014

Available from: 2024-10-14 Created: 2024-10-14 Last updated: 2025-02-20Bibliographically approved
Otomo, K., Edwards, S., Brismar, H., Susaki, E. A. & et al., . (2024). descSPIM: an affordable and easy-to-build light-sheet microscope optimized for tissue clearing techniques. Nature Communications, 15(1), Article ID 4941.
Open this publication in new window or tab >>descSPIM: an affordable and easy-to-build light-sheet microscope optimized for tissue clearing techniques
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2024 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 15, no 1, article id 4941Article in journal (Refereed) Published
Abstract [en]

Despite widespread adoption of tissue clearing techniques in recent years, poor access to suitable light-sheet fluorescence microscopes remains a major obstacle for biomedical end-users. Here, we present descSPIM (desktop-equipped SPIM for cleared specimens), a low-cost ($20,000–50,000), low-expertise (one-day installation by a non-expert), yet practical do-it-yourself light-sheet microscope as a solution for this bottleneck. Even the most fundamental configuration of descSPIM enables multi-color imaging of whole mouse brains and a cancer cell line-derived xenograft tumor mass for the visualization of neurocircuitry, assessment of drug distribution, and pathological examination by false-colored hematoxylin and eosin staining in a three-dimensional manner. Academically open-sourced (https://github.com/dbsb-juntendo/descSPIM), descSPIM allows routine three-dimensional imaging of cleared samples in minutes. Thus, the dissemination of descSPIM will accelerate biomedical discoveries driven by tissue clearing technologies.

Place, publisher, year, edition, pages
Springer Nature, 2024
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-348764 (URN)10.1038/s41467-024-49131-1 (DOI)001248267400022 ()38866781 (PubMedID)2-s2.0-85195972130 (Scopus ID)
Note

QC 20240703

Available from: 2024-06-27 Created: 2024-06-27 Last updated: 2024-07-03Bibliographically approved
Nordahl, L., Akkuratov, E. E., Heimgärtner, J., Schach, K., Meineke, B., Elsässer, S., . . . Brismar, H. (2024). Detection and quantification of Na,K-ATPase dimers in the plasma membrane of living cells by FRET-FCS. Biochimica et Biophysica Acta - General Subjects, 1868(7), Article ID 130619.
Open this publication in new window or tab >>Detection and quantification of Na,K-ATPase dimers in the plasma membrane of living cells by FRET-FCS
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2024 (English)In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1868, no 7, article id 130619Article in journal (Refereed) Published
Abstract [en]

The sodium potassium pump, Na,K-ATPase (NKA), is an integral plasma membrane protein, expressed in all eukaryotic cells. It is responsible for maintaining the transmembrane Na+ gradient and is the major determinant of the membrane potential. Self-interaction and oligomerization of NKA in cell membranes has been proposed and discussed but is still an open question. Here, we have used a combination of FRET and Fluorescence Correlation Spectroscopy, FRET-FCS, to analyze NKA in the plasma membrane of living cells. Click chemistry was used to conjugate the fluorescent labels Alexa 488 and Alexa 647 to non-canonical amino acids introduced in the NKA α1 and β1 subunits. We demonstrate that FRET-FCS can detect an order of magnitude lower concentration of green-red labeled protein pairs in a single-labeled red and green background than what is possible with cross-correlation (FCCS). We show that a significant fraction of NKA is expressed as a dimer in the plasma membrane. We also introduce a method to estimate not only the number of single and double labeled NKA, but the number of unlabeled, endogenous NKA and estimate the density of endogenous NKA at the plasma membrane to 1400 ± 800 enzymes/μm2.

Place, publisher, year, edition, pages
Elsevier BV, 2024
Keywords
FRET-FCS, NaK-ATPase, Non-canonical amino acids
National Category
Biochemistry Molecular Biology
Identifiers
urn:nbn:se:kth:diva-346157 (URN)10.1016/j.bbagen.2024.130619 (DOI)001235008700001 ()38643888 (PubMedID)2-s2.0-85191150723 (Scopus ID)
Note

QC 20240626

Available from: 2024-05-03 Created: 2024-05-03 Last updated: 2025-02-20Bibliographically approved
Senftleben, M., Bajor, A., Hirata, E., Abrahamsson, S. & Brismar, H. (2024). Fast volumetric multifocus structured illumination microscopy of subcellular dynamics in living cells. Biomedical Optics Express, 15(4), 2281-2292
Open this publication in new window or tab >>Fast volumetric multifocus structured illumination microscopy of subcellular dynamics in living cells
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2024 (English)In: Biomedical Optics Express, E-ISSN 2156-7085, Vol. 15, no 4, p. 2281-2292Article in journal (Refereed) Published
Abstract [en]

Studying the nanoscale dynamics of subcellular structures is possible with 2D structured illumination microscopy (SIM). The method allows for acquisition with improved resolution over typical widefield. For 3D samples, the acquisition speed is inherently limited by the need to acquire sequential two-dimensional planes to create a volume. Here, we present a development of multifocus SIM designed to provide high volumetric frame rate by using fast synchronized electro-optical components. We demonstrate the high volumetric imaging capacity of the microscope by recording the dynamics of microtubule and endoplasmatic reticulum in living cells at up to 2.3 super resolution volumes per second for a total volume of 30 × 30 × 1.8 µm3,.

Place, publisher, year, edition, pages
Optica Publishing Group, 2024
National Category
Condensed Matter Physics
Identifiers
urn:nbn:se:kth:diva-345742 (URN)10.1364/BOE.516261 (DOI)2-s2.0-85189452167 (Scopus ID)
Note

QC 20240425

Available from: 2024-04-18 Created: 2024-04-18 Last updated: 2025-01-08Bibliographically approved
García Casas, P., Rossini, M., Påvénius, L., Saeed, M., Arnst, N., Sonda, S., . . . Filadi, R. (2024). Simultaneous detection of membrane contact dynamics and associated Ca2+ signals by reversible chemogenetic reporters. Nature Communications, 15(1), 9775
Open this publication in new window or tab >>Simultaneous detection of membrane contact dynamics and associated Ca2+ signals by reversible chemogenetic reporters
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2024 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 15, no 1, p. 9775-Article in journal (Refereed) Published
Abstract [en]

Membrane contact sites (MCSs) are hubs allowing various cell organelles to coordinate their activities. The dynamic nature of these sites and their small size hinder analysis by current imaging techniques. To overcome these limitations, we here design a series of reversible chemogenetic reporters incorporating improved, low-affinity variants of splitFAST, and study the dynamics of different MCSs at high spatiotemporal resolution, both in vitro and in vivo. We demonstrate that these versatile reporters suit different experimental setups well, allowing one to address challenging biological questions. Using these probes, we identify a pathway in which calcium (Ca2+) signalling dynamically regulates endoplasmic reticulum-mitochondria juxtaposition, characterizing the underlying mechanism. Finally, by integrating Ca2+-sensing capabilities into the splitFAST technology, we introduce PRINCESS (PRobe for INterorganelle Ca2+-Exchange Sites based on SplitFAST), a class of reporters to simultaneously detect MCSs and measure the associated Ca2+ dynamics using a single biosensor.

Place, publisher, year, edition, pages
Springer Nature, 2024
National Category
Biophysics Biochemistry Molecular Biology
Identifiers
urn:nbn:se:kth:diva-356973 (URN)10.1038/s41467-024-52985-0 (DOI)001354231300019 ()39532847 (PubMedID)2-s2.0-85209480733 (Scopus ID)
Note

QC 20250303

Available from: 2024-11-28 Created: 2024-11-28 Last updated: 2025-03-03Bibliographically approved
Schlegel, J., Porebski, B., Andronico, L., Hanke, L., Edwards, S., Brismar, H., . . . Sezgin, E. (2023). A Multiparametric and High-Throughput Platform for Host-Virus Binding Screens. Nano Letters, 23(9), 3701-3707
Open this publication in new window or tab >>A Multiparametric and High-Throughput Platform for Host-Virus Binding Screens
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2023 (English)In: Nano Letters, ISSN 1530-6984, E-ISSN 1530-6992, Vol. 23, no 9, p. 3701-3707Article in journal (Refereed) Published
Abstract [en]

Speed is key during infectious disease outbreaks. It is essential, for example, to identify critical host binding factors to pathogens as fast as possible. The complexity of host plasma membrane is often a limiting factor hindering fast and accurate determination of host binding factors as well as high-throughput screening for neutralizing antimicrobial drug targets. Here, we describe a multiparametric and high-throughput platform tackling this bottleneck and enabling fast screens for host binding factors as well as new antiviral drug targets. The sensitivity and robustness of our platform were validated by blocking SARS-CoV-2 particles with nanobodies and IgGs from human serum samples.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023
Keywords
ACE2, flow cytometry, lipid bilayer, neuropilin-1, silica beads, virus binding
National Category
Infectious Medicine Biochemistry Molecular Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-332980 (URN)10.1021/acs.nanolett.2c04884 (DOI)000948778700001 ()36892970 (PubMedID)2-s2.0-85149779176 (Scopus ID)
Note

QC 20230724

Available from: 2023-07-24 Created: 2023-07-24 Last updated: 2025-02-20Bibliographically approved
Jess, D. U., Ramdedovic, A., Butt, L., Plagmann, I., Hoehne, M., Hackl, A., . . . Benzing, T. (2023). Advanced optical imaging reveals preferred spatial orientation of podocyte processes along the axis of glomerular capillaries. Kidney International, 104(6), 1164-1169
Open this publication in new window or tab >>Advanced optical imaging reveals preferred spatial orientation of podocyte processes along the axis of glomerular capillaries
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2023 (English)In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 104, no 6, p. 1164-1169Article in journal (Refereed) Published
Abstract [en]

Mammalian kidneys filter enormous volumes of water and small solutes, a filtration driven by the hydrostatic pressure in glomerular capillaries, which is considerably higher than in most other tissues. Interdigitating cellular processes of podocytes form the slits for fluid filtration connected by the membrane-like slit diaphragm cell junction containing a mechanosensitive ion channel complex and allow filtration while counteracting hydrostatic pressure. Several previous publications speculated that podocyte processes may display a preferable orientation on glomerular capillaries instead of a random distribution. However, for decades, the controversy over spatially oriented filtration slits could not be resolved due to technical limitations of imaging technologies. Here, we used advanced high-resolution, three-dimensional microscopy with high data throughput to assess spatial orientation of podocyte processes and filtration slits quantitatively. Filtration-slit-generating secondary processes preferentially align along the capillaries' longitudinal axis while primary processes are preferably perpendicular to the longitudinal direction. This preferential orientation required maturation in development of the mice but was lost in mice with kidney disease due to treatment with nephrotoxic serum or with underlying heterologous mutations in the podocyte foot process protein podocin. Thus, the observation that podocytes maintain a preferred spatial orientation of their processes on glomerular capillaries goes well in line with the role of podocyte foot processes as mechanical buttresses to counteract mechanical forces resulting from pressurized capillaries. Future studies are needed to establish how podocytes establish and maintain their orientation and why orientation is lost under pathological conditions.

Place, publisher, year, edition, pages
Elsevier BV, 2023
Keywords
glomerulus, podocyte, ultrafiltration
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-342067 (URN)10.1016/j.kint.2023.08.024 (DOI)001116585600001 ()37774923 (PubMedID)2-s2.0-85174456707 (Scopus ID)
Note

QC 20240110

Available from: 2024-01-10 Created: 2024-01-10 Last updated: 2025-02-20Bibliographically approved
Zysk, M., Beretta, C., Naia, L., Dakhel, A., Pavenius, L., Brismar, H., . . . Erlandsson, A. (2023). Amyloid-beta accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism. Journal of Neuroinflammation, 20(1), Article ID 43.
Open this publication in new window or tab >>Amyloid-beta accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism
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2023 (English)In: Journal of Neuroinflammation, E-ISSN 1742-2094, Vol. 20, no 1, article id 43Article in journal (Refereed) Published
Abstract [en]

BackgroundAstrocytes play a central role in maintaining brain energy metabolism, but are also tightly connected to the pathogenesis of Alzheimer's disease (AD). Our previous studies demonstrate that inflammatory astrocytes accumulate large amounts of aggregated amyloid-beta (A beta). However, in which way these A beta deposits influence their energy production remain unclear.MethodsThe aim of the present study was to investigate how A beta pathology in astrocytes affects their mitochondria functionality and overall energy metabolism. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated A beta(42) fibrils for 7 days and analyzed over time using different experimental approaches.ResultsOur results show that to maintain stable energy production, the astrocytes initially increased their mitochondrial fusion, but eventually the A beta-mediated stress led to abnormal mitochondrial swelling and excessive fission. Moreover, we detected increased levels of phosphorylated DRP-1 in the A beta-exposed astrocytes, which co-localized with lipid droplets. Analysis of ATP levels, when blocking certain stages of the energy pathways, indicated a metabolic shift to peroxisomal-based fatty acid beta-oxidation and glycolysis.ConclusionsTaken together, our data conclude that A beta pathology profoundly affects human astrocytes and changes their entire energy metabolism, which could result in disturbed brain homeostasis and aggravated disease progression.

Place, publisher, year, edition, pages
Springer Nature, 2023
Keywords
Alzheimer's disease, Glia, Lipid droplets, Mitochondria dynamics, DRP-1
National Category
Neurosciences
Identifiers
urn:nbn:se:kth:diva-324909 (URN)10.1186/s12974-023-02722-z (DOI)000935963900001 ()36803838 (PubMedID)2-s2.0-85148401898 (Scopus ID)
Note

QC 20230321

Available from: 2023-03-21 Created: 2023-03-21 Last updated: 2024-07-04Bibliographically approved
Kouznetsova, A., Liu, J. G., Valentiniene, S., Brismar, H. & Höög, C. (2022). Age-dependent aneuploidy in mammalian oocytes instigated at the second meiotic division. Aging Cell, 21(7), Article ID e13649.
Open this publication in new window or tab >>Age-dependent aneuploidy in mammalian oocytes instigated at the second meiotic division
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2022 (English)In: Aging Cell, ISSN 1474-9718, E-ISSN 1474-9726, Vol. 21, no 7, article id e13649Article in journal (Refereed) Published
Abstract [en]

Ageing severely affects the chromosome segregation process in human oocytes resulting in aneuploidy, infertility and developmental disorders. A considerable amount of segregation errors in humans are introduced at the second meiotic division. We have here compared the chromosome segregation process in young adult and aged female mice during the second meiotic division. More than half of the oocytes in aged mice displayed chromosome segregation irregularities at anaphase II, resulting in dramatically increased level of aneuploidy in haploid gametes, from 4% in young adult mice to 30% in aged mice. We find that the post-metaphase II process that efficiently corrects aberrant kinetochore-microtubule attachments in oocytes in young adult mice is approximately 10-fold less efficient in aged mice, in particular affecting chromosomes that show small inter-centromere distances at the metaphase II stage in aged mice. Our results reveal that post-metaphase II processes have critical impact on age-dependent aneuploidy in mammalian eggs. 

Place, publisher, year, edition, pages
Wiley, 2022
Keywords
Aged, Aneuploidy, Animals, Chromosome Segregation, Female, Humans, Mammals, Meiosis, Mice, Oocytes, Spindle Apparatus, anaphase, animal cell, animal experiment, animal model, Article, cell aging, centromere, controlled study, developmental disorder, gamete, infertility, kinetochore, mammal, meiotic spindle, metaphase, microtubule, mouse, nonhuman, oocyte, time lapse imaging, animal, genetics, human, age-dependent aneuploidy, chromosome, second meiotic division, segregation
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-324362 (URN)10.1111/acel.13649 (DOI)000805561500001 ()35665589 (PubMedID)2-s2.0-85131214754 (Scopus ID)
Note

QC 20230228

Available from: 2023-02-28 Created: 2023-02-28 Last updated: 2023-02-28Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0578-4003

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