SPG11 mutations observed in HSP, ALS and CMT

Posted - June 2017 in Research Highlights

Common mechanism of lipid accumulation in lysosomes

 

This important study links lysosomal dysfunction and lipid metabolism to neurodegeneration through the impairment of Spatacsin caused by SPG11 mutations that are observed in HSP, ALS (motor neurone disease) and in CMT (Charcot-Marie-Tooth) disease.

 

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.

 

SOURCE: Neurobiol Dis. 2017 Jun;102:21-37. doi: 10.1016/j.nbd.2017.02.007. Epub 2017 Feb 22. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved. PMID: 28237315

 

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

 

Branchu J1, Boutry M1, Sourd L2, Depp M2, Leone C2, Corriger A2, Vallucci M2, Esteves T2, Matusiak R1, Dumont M1, Muriel MP1, Santorelli FM3, Brice A1, El Hachimi KH2, Stevanin G4, Darios F5.

 

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: [email protected]

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: [email protected]

Comments on this story

  1. Carina posted at 10:00 am on 4 August 2017Reply

    A quick question about this research does that mean SPG11 mutations are linked to Cmt and ALS? So mutations in that gene can cause cmt and ALS?

    • Editor posted at 11:16 am on 6 August 2017Reply

      Editor’s Note: The brief answer is yes, that is what is being stated in this study. It should be noted that mutations in SPG11 are responsible for rare forms of both CMT and ALS.

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