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Article: Clinically approved immunomodulators ameliorate behavioral changes in a mouse model of hereditary spastic paraplegia type 11.

Hörner, Michaela / Popp, Sandy / Branchu, Julien / Stevanin, Giovanni / Darios, Frédéric / Klebe, Stephan / Groh, Janos / Martini, Rudolf

Frontiers in neuroscience

2024 Volume 18, Page(s) 1299554

Abstract: We have previously demonstrated that neuroinflammation by the adaptive immune system acts as a robust and targetable disease amplifier in a mouse model of Spastic Paraplegia, type 11 (SPG11), a complicated form of Hereditary Spastic Paraplegia (HSP). ... ...

Abstract	We have previously demonstrated that neuroinflammation by the adaptive immune system acts as a robust and targetable disease amplifier in a mouse model of Spastic Paraplegia, type 11 (SPG11), a complicated form of Hereditary Spastic Paraplegia (HSP). While we identified an impact of neuroinflammation on distinct neuropathological changes and gait performance, neuropsychological features, typical and clinically highly relevant symptoms of complicated HSPs, were not addressed. Here we show that the corresponding SPG11 mouse model shows distinct behavioral abnormalities, particularly related to social behavior thus partially reflecting the neuropsychological changes in patients. We provide evidence that some behavioral abnormalities can be mitigated by genetic inactivation of the adaptive immune system. Translating this into a clinically applicable approach, we show that treatment with the established immunomodulators fingolimod or teriflunomide significantly attenuates distinct behavioral abnormalities, with the most striking effect on social behavior. This study links neuroinflammation to behavioral abnormalities in a mouse model of SPG11 and may thus pave the way for using immunomodulators as a treatment approach for SPG11 and possibly other complicated forms of HSP with neuropsychological involvement.
Language	English
Publishing date	2024-02-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2024.1299554
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Article ; Online: Therapeutische Erreichbarkeit der Retina bei systemischen immunmodulatorischen Ansätzen bei Mausmodellen für neuronale Ceroid-Lipofuszinosen : Kommentar zu Bartsch et al., Der Ophthalmologe, 02/2021.

Martini, Rudolf / Ach, Thomas / Rostasy, Kevin / Groh, Janos

Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft

2021 Volume 118, Issue 7, Page(s) 767–768

Title translation	Therapeutic accessibility of the retina in systemic immunomodulatory approaches in mouse models for neuronal ceroid lipofuscinosis : Comments on Bartsch et al., Der Ophthalmologe 02/2021.
MeSH term(s)	Animals ; Disease Models, Animal ; Mice ; Neuronal Ceroid-Lipofuscinoses/genetics ; Neuronal Ceroid-Lipofuscinoses/therapy ; Retina
Language	German
Publishing date	2021-06-02
Publishing country	Germany
Document type	Letter ; Comment
ZDB-ID	1105167-x
ISSN	1433-0423 ; 0941-293X
ISSN (online)	1433-0423
ISSN	0941-293X
DOI	10.1007/s00347-021-01418-0
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Article ; Online: Immune modulation attenuates infantile neuronal ceroid lipofuscinosis in mice before and after disease onset.

Groh, Janos / Berve, Kristina / Martini, Rudolf

Brain communications

2021 Volume 3, Issue 2, Page(s) fcab047

Abstract: Targeting neuroinflammation in models for infantile and juvenile forms of neuronal ceroid lipofuscinosis (NCL, CLN disease) with the clinically established immunomodulators fingolimod and teriflunomide significantly attenuates the neurodegenerative ... ...

Abstract	Targeting neuroinflammation in models for infantile and juvenile forms of neuronal ceroid lipofuscinosis (NCL, CLN disease) with the clinically established immunomodulators fingolimod and teriflunomide significantly attenuates the neurodegenerative phenotype when applied preventively, i.e. before the development of substantial neural damage and clinical symptoms. Here, we show that in a mouse model for the early onset and rapidly progressing CLN1 form, more complex clinical phenotypes like disturbed motor coordination and impaired visual acuity are also ameliorated by immunomodulation. Moreover, we show that the disease outcome can be attenuated even when fingolimod and teriflunomide treatment starts after disease onset, i.e. when neurodegeneration is ongoing and clinical symptoms are detectable. In detail, treatment with either drug led to a reduction in T-cell numbers and microgliosis in the CNS, although not to the same extent as upon preventive treatment. Pharmacological immunomodulation was accompanied by a reduction of axonal damage, neuron loss and astrogliosis in the retinotectal system and by reduced brain atrophy. Accordingly, the frequency of myoclonic jerks and disturbed motor coordination were attenuated. Overall, disease alleviation was remarkably substantial upon therapeutic treatment with both drugs, although less robust than upon preventive treatment. To test the relevance of putative immune-independent mechanisms of action in this model, we treated CLN1 mice lacking mature T- and B-lymphocytes. Immunodeficient CLN1 mice showed, as previously reported, an improved neurological phenotype in comparison with genuine CLN1 mice which could not be further alleviated by either of the drugs, reflecting a predominantly immune-related therapeutic mechanism of action. The present study supports and strengthens our previous view that repurposing clinically approved immunomodulators may alleviate the course of CLN1 disease in human patients, even though diagnosis usually occurs when symptoms have already emerged.
Language	English
Publishing date	2021-03-21
Publishing country	England
Document type	Journal Article
ISSN	2632-1297
ISSN (online)	2632-1297
DOI	10.1093/braincomms/fcab047
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Article ; Online: Cytotoxic CNS-associated T cells drive axon degeneration by targeting perturbed oligodendrocytes in

Abdelwahab, Tassnim / Stadler, David / Knöpper, Konrad / Arampatzi, Panagiota / Saliba, Antoine-Emmanuel / Kastenmüller, Wolfgang / Martini, Rudolf / Groh, Janos

iScience

2023 Volume 26, Issue 5, Page(s) 106698

Abstract: Myelin defects lead to neurological dysfunction in various diseases and in normal aging. Chronic neuroinflammation often contributes to axon-myelin damage in these conditions and can be initiated and/or sustained by perturbed myelinating glia. We have ... ...

Abstract	Myelin defects lead to neurological dysfunction in various diseases and in normal aging. Chronic neuroinflammation often contributes to axon-myelin damage in these conditions and can be initiated and/or sustained by perturbed myelinating glia. We have previously shown that distinct
Language	English
Publishing date	2023-04-19
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.106698
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Article ; Online: Early targeting of endoneurial macrophages alleviates the neuropathy and affects abnormal Schwann cell differentiation in a mouse model of Charcot-Marie-Tooth 1A.

Klein, Dennis / Groh, Janos / Yuan, Xidi / Berve, Kristina / Stassart, Ruth / Fledrich, Robert / Martini, Rudolf

Glia

2022 Volume 70, Issue 6, Page(s) 1100–1116

Abstract: We have previously shown that targeting endoneurial macrophages with the orally applied CSF-1 receptor specific kinase (c-FMS) inhibitor PLX5622 from the age of 3 months onwards led to a substantial alleviation of the neuropathy in mouse models of ... ...

Abstract	We have previously shown that targeting endoneurial macrophages with the orally applied CSF-1 receptor specific kinase (c-FMS) inhibitor PLX5622 from the age of 3 months onwards led to a substantial alleviation of the neuropathy in mouse models of Charcot-Marie-Tooth (CMT) 1X and 1B disease, which are genetically-mediated nerve disorders not treatable in humans. The same approach failed in a model of CMT1A (PMP22-overexpressing mice, line C61), representing the most frequent form of CMT. This was unexpected since previous studies identified macrophages contributing to disease severity in the same CMT1A model. Here we re-approached the possibility of alleviating the neuropathy in a model of CMT1A by targeting macrophages at earlier time points. As a proof-of-principle experiment, we genetically inactivated colony-stimulating factor-1 (CSF-1) in CMT1A mice, which resulted in lower endoneurial macrophage numbers and alleviated the neuropathy. Based on these observations, we pharmacologically ablated macrophages in newborn CMT1A mice by feeding their lactating mothers with chow containing PLX5622, followed by treatment of the respective progenies after weaning until the age of 6 months. We found that peripheral neuropathy was substantially alleviated after early postnatal treatment, leading to preserved motor function in CMT1A mice. Moreover, macrophage depletion affected the altered Schwann cell differentiation phenotype. These findings underscore the targetable role of macrophage-mediated inflammation in peripheral nerves of inherited neuropathies, but also emphasize the need for an early treatment start confined to a narrow therapeutic time window in CMT1A models and potentially in respective patients.
MeSH term(s)	Animals ; Cell Differentiation ; Charcot-Marie-Tooth Disease/genetics ; Female ; Humans ; Lactation ; Macrophages/metabolism ; Mice ; Peripheral Nerves/metabolism
Language	English
Publishing date	2022-02-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639414-0
ISSN	1098-1136 ; 0894-1491
ISSN (online)	1098-1136
ISSN	0894-1491
DOI	10.1002/glia.24158
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Article ; Online: Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment.

Groh, Janos / Martini, Rudolf

Glia

2017 Volume 65, Issue 9, Page(s) 1407–1422

Abstract: Genetically caused neurological disorders of the central nervous system (CNS) are usually orphan diseases with poor or even fatal clinical outcome and few or no treatments that will improve longevity or at least quality of life. Neuroinflammation is ... ...

Abstract	Genetically caused neurological disorders of the central nervous system (CNS) are usually orphan diseases with poor or even fatal clinical outcome and few or no treatments that will improve longevity or at least quality of life. Neuroinflammation is common to many of these disorders, despite the fact that a plethora of distinct mutations and molecular changes underlie the disorders. In this article, data from corresponding animal models are analyzed to define the roles of innate and adaptive inflammation as modifiers and amplifiers of disease. We describe both common and distinct patterns of neuroinflammation in genetically mediated CNS disorders and discuss the contrasting mechanisms that lead to adverse versus neuroprotective effects. Moreover, we identify the juxtaparanode as a neuroanatomical compartment commonly associated with inflammatory cells and ongoing axonopathic changes, in models of diverse diseases. The identification of key immunological effector pathways that amplify neuropathic features should lead to realistic possibilities for translatable therapeutic interventions using existing immunomodulators. Moreover, evidence emerges that neuroinflammation is not only able to modify primary neural damage-related symptoms but also may lead to unexpected clinical outcomes such as neuropsychiatric syndromes.
Language	English
Publishing date	2017-09
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	639414-0
ISSN	1098-1136 ; 0894-1491
ISSN (online)	1098-1136
ISSN	0894-1491
DOI	10.1002/glia.23162
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Article ; Online: More than one millennium (2nd-16th century CE) of the White Plague in the Carpathian Basin - New cases, expanding knowledge.

Kiss, Krisztián / Bálint, Marianna / Gémes, Anett / Marcsik, Antónia / Dávid, Áron / Évinger, Sándor / Gróf, Péter / Gróh, Dániel / Gyenesei, Katalin Éva / János, István / Kolozsi, Barbara / Kovács, Loránd Olivér / Mateovics-László, Orsolya / Líbor, Csilla / Merczi, Mónika / Molnár, Erika / Németh, Csilla Emese / Pálfi, György / Perémi, Ágota /

Rácz, Zsófia / Spekker, Olga / Szőke, Béla Miklós / Tóth, István Zsolt / Tóth, Zoltán / Hajdu, Tamás / Szeniczey, Tamás

Tuberculosis (Edinburgh, Scotland)

2023 Volume 143S, Page(s) 102387

Abstract: The causative agent of tuberculosis is still a widespread pathogen, which caused the death of ca. 1.6 million people globally in 2021. The paleopathological study of human remains revealed the antiquity of the disease and its continuous presence ... ...

Abstract	The causative agent of tuberculosis is still a widespread pathogen, which caused the death of ca. 1.6 million people globally in 2021. The paleopathological study of human remains revealed the antiquity of the disease and its continuous presence throughout the history of humankind. The Carpathian Basin has always been a biocultural melting pot, since it has seen several migrations over the centuries, and served as a location of admixture and interaction for numerous populations of different cultures. Thus, this geographical territory is ideal for the examination of the coevolutionary processes of hosts and their pathogens. We aimed to reveal the spatial and temporal distribution of tuberculosis cases excavated inside the borders of Hungary between the 2nd and 16th centuries CE. We established a comprehensive database by collecting 114 already published cases and introducing 39 new cases. The involved cases include those that have been confirmed by different molecular methods, as well as possible infections that were identified based on the presence of macromorphological and radiological alterations. The progress of future molecular and paleopathological studies can be facilitated by our dataset, as it presents spatial and temporal information concerning the spread of the disease in the Carpathian Basin, as well as the biological profile and detailed paleopathological description of lesions illustrated by photo- and radiographs.
MeSH term(s)	Humans ; Mycobacterium tuberculosis/genetics ; DNA, Bacterial ; Tuberculosis, Osteoarticular/history ; Hungary ; Paleopathology/methods
Chemical Substances	DNA, Bacterial
Language	English
Publishing date	2023-11-25
Publishing country	Scotland
Document type	Case Reports ; Journal Article ; Review
ZDB-ID	2046804-0
ISSN	1873-281X ; 1472-9792
ISSN (online)	1873-281X
ISSN	1472-9792
DOI	10.1016/j.tube.2023.102387
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Article ; Online: Cytotoxic CNS-associated T cells drive axon degeneration by targeting perturbed oligodendrocytes in PLP1 mutant mice

Tassnim Abdelwahab / David Stadler / Konrad Knöpper / Panagiota Arampatzi / Antoine-Emmanuel Saliba / Wolfgang Kastenmüller / Rudolf Martini / Janos Groh

iScience, Vol 26, Iss 5, Pp 106698- (2023)

2023

Abstract: Summary: Myelin defects lead to neurological dysfunction in various diseases and in normal aging. Chronic neuroinflammation often contributes to axon-myelin damage in these conditions and can be initiated and/or sustained by perturbed myelinating glia. ... ...

Abstract	Summary: Myelin defects lead to neurological dysfunction in various diseases and in normal aging. Chronic neuroinflammation often contributes to axon-myelin damage in these conditions and can be initiated and/or sustained by perturbed myelinating glia. We have previously shown that distinct PLP1 mutations result in neurodegeneration that is largely driven by adaptive immune cells. Here we characterize CD8+ CNS-associated T cells in myelin mutants using single-cell transcriptomics and identify population heterogeneity and disease-associated changes. We demonstrate that early sphingosine-1-phosphate receptor modulation attenuates T cell recruitment and neural damage, while later targeting of CNS-associated T cell populations is inefficient. Applying bone marrow chimerism and utilizing random X chromosome inactivation, we provide evidence that axonal damage is driven by cytotoxic, antigen specific CD8+ T cells that target mutant myelinating oligodendrocytes. These findings offer insights into neural-immune interactions and are of translational relevance for neurological conditions associated with myelin defects and neuroinflammation.
Keywords	Molecular neuroscience ; Components of the immune system ; Model organism ; Science ; Q
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice.

Berve, Kristina / West, Brian L / Martini, Rudolf / Groh, Janos

Journal of neuroinflammation

2020 Volume 17, Issue 1, Page(s) 323

Abstract: Background: The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage ...

Abstract	Background: The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1 Methods: We applied treatment with PLX3397 (150 ppm in the chow), a potent inhibitor of the colony stimulating factor-1 receptor (CSF-1R) to target innate immune cells in CLN1 mice. Experimental long-term treatment was non-invasively monitored by longitudinal optical coherence tomography and rotarod analysis, as well as analysis of visual acuity, myoclonic jerks, and survival. Treatment effects regarding neuroinflammation, neural damage, and neurodegeneration were subsequently analyzed by histology and immunohistochemistry. Results: We show that PLX3397 treatment attenuates neuroinflammation in CLN1 mice by depleting pro-inflammatory microglia/macrophages. This leads to a reduction of T lymphocyte recruitment, an amelioration of axon damage and neuron loss in the retinotectal system, as well as reduced thinning of the inner retina and total brain atrophy. Accordingly, long-term treatment with the inhibitor also ameliorates clinical outcomes in CLN1 mice, such as impaired motor coordination, visual acuity, and myoclonic jerks. However, we detected a sex- and region-biased efficacy of CSF-1R inhibition, with male microglia/macrophages showing higher responsiveness toward depletion, especially in the gray matter of the CNS. This results in a better treatment outcome in male Ppt1 Conclusions: Our results demonstrate a detrimental impact of innate immune reactions in the CNS of CLN1 mice. These findings provide insights into CLN pathogenesis and may guide in the design of immunomodulatory treatment strategies.
MeSH term(s)	Aminopyridines/pharmacology ; Aminopyridines/therapeutic use ; Animals ; Brain/drug effects ; Brain/pathology ; Disease Models, Animal ; Female ; Macrophages/drug effects ; Macrophages/pathology ; Male ; Mice ; Microglia/drug effects ; Microglia/pathology ; Nerve Degeneration/drug therapy ; Nerve Degeneration/immunology ; Nerve Degeneration/pathology ; Neuronal Ceroid-Lipofuscinoses/drug therapy ; Neuronal Ceroid-Lipofuscinoses/immunology ; Neuronal Ceroid-Lipofuscinoses/pathology ; Neurons/drug effects ; Neurons/pathology ; Pyrroles/pharmacology ; Pyrroles/therapeutic use ; Retina/drug effects ; Retina/pathology ; Sex Factors ; T-Lymphocytes/drug effects ; T-Lymphocytes/pathology ; Tomography, Optical Coherence
Chemical Substances	Aminopyridines ; Pyrroles ; pexidartinib (6783M2LV5X)
Language	English
Publishing date	2020-10-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-020-01996-x
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Article ; Online: Microglia-mediated demyelination protects against CD8

Groh, Janos / Abdelwahab, Tassnim / Kattimani, Yogita / Hörner, Michaela / Loserth, Silke / Gudi, Viktoria / Adalbert, Robert / Imdahl, Fabian / Saliba, Antoine-Emmanuel / Coleman, Michael / Stangel, Martin / Simons, Mikael / Martini, Rudolf

Nature communications

2023 Volume 14, Issue 1, Page(s) 6911

Abstract: Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal ... ...

Abstract	Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8
MeSH term(s)	Animals ; Mice ; Axons/metabolism ; CD8-Positive T-Lymphocytes ; Demyelinating Diseases/metabolism ; Microglia ; Myelin Sheath/metabolism ; Neuroinflammatory Diseases
Chemical Substances	Plp1 protein, mouse
Language	English
Publishing date	2023-10-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-42570-2
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