Neuroinflammation important in SPG11

Responsive to drug treatment in animal testing

Treatment of SPG11 mice with drugs that reduce neuroinflammation significantly improved their walking ability even later in disease progression. Ataxia symptoms were also reduced, however muscle weakness was not improved.

The HSPs are not generally considered to be diseases where inflammation is an important part of the disease-causing process, unlike Multiple Sclerosis and Motor Neuron Disease. Recent findings in SPG2 and now SPG11 show that inflammation is an important part of the disease process in at least these forms of HSP.

Abstract

Pharmacological targeting of neuroinflammation in distinct models of genetically mediated disorders of the central nervous system (CNS) has been shown to attenuate disease outcome significantly. These include mouse models mimicking distinct subtypes of neuronal ceroid lipofuscinoses (NCL, CLN diseases) as well as hereditary spastic paraplegia type 2 (HSP/SPG2).

We here show in a model of another, complicated HSP form (SPG11) that there is neuroinflammation in distinct compartments of the diseased CNS. Using a proof-of-principle experiment, we provide evidence that genetically targeting the adaptive immune system dampens disease progression including gait disturbance, demonstrating a pathogenic impact of neuroinflammation.

Translating these studies into a clinically applicable approach, we show that the established immunomodulators fingolimod and teriflunomide significantly attenuate the neurodegenerative phenotype and improve gait performance in the SPG11 model, even when applied relatively late during disease progression. Particularly abnormalities in gait coordination, representing ataxia, could be attenuated, while features indicative of reduced strength during walking did not respond to treatment.

Our study identifies neuroinflammation by the adaptive immune system as a robust and targetable disease amplifier in a mouse model of SPG11 and may thus pave the way for a translational approach in humans implicating approved immunomodulators.

SOURCE:  Exp Neurol. 2022 Sep;355:114119. doi: 10.1016/j.expneurol.2022.114119. Epub 2022 May 20. PMID: 35605667 Copyright © 2022 Elsevier Inc. All rights reserved.

CNS-associated T-lymphocytes in a mouse model of Hereditary Spastic Paraplegia type 11 (SPG11) are therapeutic targets for established immunomodulators

Michaela Hörner  1 Janos Groh  2 Dennis Klein  3 Winfried Ilg  4 Ludger Schöls  5 Sara Dos Santos  6 Anna Bergmann  7 Stephan Klebe  8 Margaux Cauhape  9 Julien Branchu  10 Khalid Hamid El Hachimi  11 Giovanni Stevanin  12 Frédéric Darios  13 Rudolf Martini  14

1. Section of Developmental Neurobiology, Department of Neurology, University Hospital, Würzburg, 97080, Würzburg, Germany. Electronic address: [email protected]

2. Section of Developmental Neurobiology, Department of Neurology, University Hospital, Würzburg, 97080, Würzburg, Germany. Electronic address: [email protected]

3. Section of Developmental Neurobiology, Department of Neurology, University Hospital, Würzburg, 97080, Würzburg, Germany. Electronic address: [email protected]

4. Section Computational Sensomotorics, Hertie Institute for Clinical Brain Research and Centre of Neurology, Tübingen, Germany. Electronic address: [email protected]

5. Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), DZNE, Tübingen, Germany. Electronic address: [email protected]

6. Section of Developmental Neurobiology, Department of Neurology, University Hospital, Würzburg, 97080, Würzburg, Germany. Electronic address: [email protected]

7. Section of Developmental Neurobiology, Department of Neurology, University Hospital, Würzburg, 97080, Würzburg, Germany. Electronic address: [email protected]

8. Department of Neurology, University Hospital Essen, 45147 Essen, Germany. Electronic address: [email protected]

9. Sorbonne Université, Institut du Cerveau – Paris Brain Institute, Inserm U1127, CNRS UMR 7225, 75013 Paris, France. Electronic address: [email protected]

10. Sorbonne Université, Institut du Cerveau – Paris Brain Institute, Inserm U1127, CNRS UMR 7225, 75013 Paris, France; EVerZom, 75006 Paris, France. Electronic address: [email protected]

11. Sorbonne Université, Institut du Cerveau – Paris Brain Institute, Inserm U1127, CNRS UMR 7225, 75013 Paris, France. Electronic address: [email protected]

12. Sorbonne Université, Institut du Cerveau – Paris Brain Institute, Inserm U1127, CNRS UMR 7225, 75013 Paris, France; Université de Bordeaux, INCIA, CNRS, EPHE, 33000 Bordeaux, France. Electronic address: [email protected]

13. Sorbonne Université, Institut du Cerveau – Paris Brain Institute, Inserm U1127, CNRS UMR 7225, 75013 Paris, France. Electronic address: [email protected]

14. Section of Developmental Neurobiology, Department of Neurology, University Hospital, Würzburg, 97080, Würzburg, Germany. Electronic address: [email protected]

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