Decreasing ganglioside synthesis delays motor and cognitive symptom onset in Spg11 knockout mice
Neurobiology of Disease. 2024-09-01; 199: 106564
DOI: 10.1016/j.nbd.2024.106564
1. Neurobiol Dis. 2024 Sep;199:106564. doi: 10.1016/j.nbd.2024.106564. Epub 2024
Jun 12.
Decreasing ganglioside synthesis delays motor and cognitive symptom onset in
Spg11 knockout mice.
Fortier M(1), Cauhapé M(1), Buono S(2), Becker J(2), Menuet A(2), Branchu J(1),
Ricca I(3), Mero S(3), Dorgham K(4), El Hachimi KH(5), Dobrenis K(6), Colsch
B(7), Samaroo D(1), Devaux M(1), Durr A(1), Stevanin G(8), Santorelli FM(3),
Colombo S(2), Cowling B(2), Darios F(9).
Author information:
(1)Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), INSERM
U1127, CNRS UMR 7225, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris,
France.
(2)Dynacure SA (now Flamingo Therapeutics NV), Illkirch, France.
(3)Molecular Medicine, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy.
(4)Sorbonne Université, INSERM, Centre d’Immunologie et des Maladies
Infectieuses-Paris (CIMI-Paris), Paris, France.
(5)Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), INSERM
U1127, CNRS UMR 7225, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris,
France; EPHE, PSL Research University, Paris, France.
(6)Dominick P. Purpura Department of Neuroscience, Albert Einstein College of
Medicine, Bronx, NY 10461, USA.
(7)Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies
pour la Santé, MetaboHUB, Gif sur Yvette, France.
(8)Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), INSERM
U1127, CNRS UMR 7225, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris,
France; EPHE, PSL Research University, Paris, France; University of Bordeaux,
CNRS, INCIA, UMR 5287, NRGen Team, Bordeaux, France.
(9)Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), INSERM
U1127, CNRS UMR 7225, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris,
France. Electronic address: .
Biallelic variants in the SPG11 gene account for the most common form of
autosomal recessive hereditary spastic paraplegia characterized by motor and
cognitive impairment, with currently no therapeutic option. We previously
observed in a Spg11 knockout mouse that neurodegeneration is associated with
accumulation of gangliosides in lysosomes. To test whether a substrate reduction
therapy could be a therapeutic option, we downregulated the key enzyme involved
in ganglioside biosynthesis using an AAV-PHP.eB viral vector expressing a miRNA
targeting St3gal5. Downregulation of St3gal5 in Spg11 knockout mice prevented
the accumulation of gangliosides, delayed the onset of motor and cognitive
symptoms, and prevented the upregulation of serum levels of neurofilament light
chain, a biomarker widely used in neurodegenerative diseases. Importantly,
similar results were observed when Spg11 knockout mice were administrated
venglustat, a pharmacological inhibitor of glucosylceramide synthase expected to
decrease ganglioside synthesis. Downregulation of St3gal5 or venglustat
administration in Spg11 knockout mice strongly decreased the formation of axonal
spheroids, previously associated with impaired trafficking. Venglustat had
similar effect on cultured human SPG11 neurons. In conclusion, this work
identifies the first disease-modifying therapeutic strategy in SPG11, and
provides data supporting its relevance for therapeutic testing in SPG11
patients.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nbd.2024.106564
PMID: 38876323 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest G.S. received
a grant from the PSL-Biogen program 2019–2023, unrelated to this work. S.B.,
J.Be., A.M., S.C. and B.Cow. were employees of Dynacure SA. J.Br., G.S. and F.D.
are authors of a patent related to this work.