title: Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration.
abstract: Mutations in SPG11 account for the most common form of autosomal recessive hereditary spastic paraplegia (HSP), characterized by a gait disorder associated with various brain alterations. Mutations in the same gene are also responsible for rare forms of Charcot-Marie-Tooth (CMT) disease and progressive juvenile-onset amyotrophic lateral sclerosis (ALS). To elucidate the physiopathological mechanisms underlying these human pathologies, we disrupted the Spg11 gene in mice by inserting stop codons in exon 32, mimicking the most frequent mutations found in patients. The Spg11 knockout mouse developed early-onset motor impairment and cognitive deficits. These behavioral deficits were associated with progressive brain atrophy with the loss of neurons in the primary motor cortex, cerebellum and hippocampus, as well as with accumulation of dystrophic axons in the corticospinal tract. Spinal motor neurons also degenerated and this was accompanied by fragmentation of neuromuscular junctions and muscle atrophy. This new Spg11 knockout mouse therefore recapitulates the full range of symptoms associated with SPG11 mutations observed in HSP, ALS and CMT patients. Examination of the cellular alterations observed in this model suggests that the loss of spatacsin leads to the accumulation of lipids in lysosomes by perturbing their clearance from these organelles. Altogether, our results link lysosomal dysfunction and lipid metabolism to neurodegeneration and pinpoint a critical role of spatacsin in lipid turnover.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Branchu
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Boutry
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France; Ecole Pratique des Hautes Etudes, PSL Research University, Laboratoire de Neurogénétique, F-75013 Paris, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Sourd
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France; Ecole Pratique des Hautes Etudes, PSL Research University, Laboratoire de Neurogénétique, F-75013 Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Depp
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France; Ecole Pratique des Hautes Etudes, PSL Research University, Laboratoire de Neurogénétique, F-75013 Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Leone
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France; Ecole Pratique des Hautes Etudes, PSL Research University, Laboratoire de Neurogénétique, F-75013 Paris, France.
authors.forename: Alexandrine
authors.initials: A
authors.lastname: Corriger
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France; Ecole Pratique des Hautes Etudes, PSL Research University, Laboratoire de Neurogénétique, F-75013 Paris, France.
authors.forename: Maeva
authors.initials: M
authors.lastname: Vallucci
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France; Ecole Pratique des Hautes Etudes, PSL Research University, Laboratoire de Neurogénétique, F-75013 Paris, France.
authors.forename: Typhaine
authors.initials: T
authors.lastname: Esteves
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Matusiak
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Dumont
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Muriel
authors.affiliation: Molecular Medicine, IRCCS Stella Maris Foundation, Calambronne, I-56100 Pisa, Italy.
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France; Ecole Pratique des Hautes Etudes, PSL Research University, Laboratoire de Neurogénétique, F-75013 Paris, France.
authors.forename: Khalid Hamid
authors.initials: KH
authors.lastname: El Hachimi
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France; Ecole Pratique des Hautes Etudes, PSL Research University, Laboratoire de Neurogénétique, F-75013 Paris, France. Electronic address: giovanni.stevanin@upmc.fr.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France; Inserm, U1127, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, F-75013 Paris, France. Electronic address: frederic.darios@upmc.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Darios
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D016472:Motor Neuron Disease / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D011506:Proteins; C000597153:SPG11 protein, mouse
keywords: Lipids; Lysosome; Motor neuron; Neurodegeneration; SPG11