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

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.

• Authors: Michaela Hörner, Janos Groh, Dennis Klein, Winfried Ilg, Ludger Schöls, Sara Dos Santos, Anna Bergmann, Stephan Klebe, Margaux Cauhape, Julien Branchu, Khalid Hamid El Hachimi, Giovanni Stevanin, Frédéric Darios, Rudolf Martini
• Journal: Experimental neurology (Exp Neurol) Vol. 355 Pg. 114119 (09 2022) ISSN: 1090-2430 [Electronic] United States
• PMID: 35605667 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Immunologic Factors
• Proteins
• SPG11 protein, mouse

Topics

• Animals
• Central Nervous System (pathology)
• Disease Models, Animal
• Disease Progression
• Immunologic Factors (pharmacology, therapeutic use)
• Mice
• Mutation
• Proteins (genetics)
• Spastic Paraplegia, Hereditary (drug therapy, genetics, pathology)
• T-Lymphocytes (pathology)