CNS-associated T-lymphocytes in a mouse model of Hereditary Spastic Paraplegia type 11 (SPG11) are therapeutic targets for established immunomodulators
Experimental Neurology. 2022-09-01; 355: 114119
DOI: 10.1016/j.expneurol.2022.114119
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Hörner M(1), Groh J(2), Klein D(3), Ilg W(4), Schöls L(5), Dos Santos S(6),
Bergmann A(7), Klebe S(8), Cauhape M(9), Branchu J(10), El Hachimi KH(11),
Stevanin G(12), Darios F(13), Martini R(14).
Author information:
(1)Section of Developmental Neurobiology, Department of Neurology, University
Hospital, Würzburg, 97080, Würzburg, Germany. Electronic address:
.
(2)Section of Developmental Neurobiology, Department of Neurology, University
Hospital, Würzburg, 97080, Würzburg, Germany. Electronic address: .
(3)Section of Developmental Neurobiology, Department of Neurology, University
Hospital, Würzburg, 97080, Würzburg, Germany. Electronic address:
.
(4)Section Computational Sensomotorics, Hertie Institute for Clinical Brain
Research and Centre of Neurology, Tübingen, Germany. Electronic address:
.
(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:
.
(6)Section of Developmental Neurobiology, Department of Neurology, University
Hospital, Würzburg, 97080, Würzburg, Germany. Electronic address:
.
(7)Section of Developmental Neurobiology, Department of Neurology, University
Hospital, Würzburg, 97080, Würzburg, Germany. Electronic address:
.
(8)Department of Neurology, University Hospital Essen, 45147 Essen, Germany.
Electronic address: .
(9)Sorbonne Université, Institut du Cerveau – Paris Brain Institute, Inserm
U1127, CNRS UMR 7225, 75013 Paris, France. Electronic address:
.
(10)Sorbonne Université, Institut du Cerveau – Paris Brain Institute, Inserm
U1127, CNRS UMR 7225, 75013 Paris, France; EVerZom, 75006 Paris, France.
Electronic address: .
(11)Sorbonne Université, Institut du Cerveau – Paris Brain Institute, Inserm
U1127, CNRS UMR 7225, 75013 Paris, France. Electronic address:
.
(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: .
(13)Sorbonne Université, Institut du Cerveau – Paris Brain Institute, Inserm
U1127, CNRS UMR 7225, 75013 Paris, France. Electronic address:
.
(14)Section of Developmental Neurobiology, Department of Neurology, University
Hospital, Würzburg, 97080, Würzburg, Germany. Electronic address:
.
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.
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