Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration.

Julien Branchu, Maxime Boutry, Laura Sourd, Marine Depp, Céline Leone, Alexandrine Corriger, Maeva Vallucci, Typhaine Esteves, Raphaël Matusiak, Magali Dumont, Marie-Paule Muriel, Filippo M. Santorelli, Alexis Brice, Khalid Hamid El Hachimi, Giovanni Stevanin, Frédéric Darios
Neurobiology of Disease. 2017-06-01; 102: 21-37
DOI: 10.1016/j.nbd.2017.02.007

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1. Neurobiol Dis. 2017 Jun;102:21-37. doi: 10.1016/j.nbd.2017.02.007. Epub 2017 Feb
22.

Loss of spatacsin function alters lysosomal lipid clearance leading to upper and
lower motor neuron degeneration.

Branchu J(1), Boutry M(1), Sourd L(2), Depp M(2), Leone C(2), Corriger A(2),
Vallucci M(2), Esteves T(2), Matusiak R(1), Dumont M(1), Muriel MP(1), Santorelli
FM(3), Brice A(1), El Hachimi KH(2), Stevanin G(4), Darios F(5).

Author information:
(1)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.
(2)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.
(3)Molecular Medicine, IRCCS Stella Maris Foundation, Calambronne, I-56100 Pisa,
Italy.
(4)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:
.
(5)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: .

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.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.nbd.2017.02.007
PMCID: PMC5391847
PMID: 28237315 [Indexed for MEDLINE]

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