Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration. Branchu et al, Neurobiol dis 2017



Spg11 knockout mouse recapitulates the motor and cognitive symptoms observed in patients.

Spg11 knockout mouse presents neurodegeneration in cortex, cerebellum, hippocampus and spinal cord.

Loss of spatacsin, the product of Spg11, leads to early lysosomal dysfunction.

Loss of spatacsin promotes lipid accumulation in lysosomes.

Julien Branchu,a Maxime Boutry,a Laura Sourd,a,b Marine Depp,a,b Céline Leone,a,b  Alexandrine Corriger,a,b Maeva Vallucci,a,b Typhaine Esteves,a,b Raphaël Matusiak,a Magali Dumont,a Marie-Paule Muriel,a Filippo M. Santorelli,c Alexis Brice,a Khalid H. El Hachimi,a,b Giovanni Stevanin,a,b,# Frédéric Darios,a,#

  • a Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Inserm, U1127, CNRS, UMR 7225, F-75013 Paris, France
  • b Ecole Pratique des Hautes Etudes, PSL Research University, Laboratoire de Neurogénétique, F-75013 Paris, France
  • c Molecular Medicine, IRCCS Stella Maris Foundation, Calambronne, I-56100 Pisa, Italy
  • # co-corresponding authors

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.



Figure: Loss of spatacsin promotes the accumulation of lipids in lipofuscine-like structures in neurons. (A) Electron micrographs of cortical neurons from Spg11+/+ and Spg11−/− mice at two or 16 months. Red lines indicate the plasma membrane of neurons. Arrowheads indicate low-density structures consistent with lipid droplets. Scale bars: 5 μm (upper panels) and 1 μm (lower panels). (B) Electron micrographs of spinal cord motor neurons from two-month old Spg11+/+ and Spg11−/− mice. Red lines indicate the plasma membrane of motor neurons. White squares indicate the zone shown at higher magnification in the insets. Scale bars: 5 μm. (C) Cathepsin D immunoelectron microscopy revealed with diaminobenzidine (DAB), showing the presence of DAB precipitates in lipofuscin-like structures (red arrowheads). Note the presence of DAB precipitates in a lysosome (red arrow). Asterisks indicate low-density structures compatible with lipid droplets. Scale bar: 500 nm. (D) Electron microscopy images of cortical neurons in the brain of an SPG11 patient (duration of disease: 10 years; age at death: 32 years), showing the accumulation of lipofuscin (arrowheads). The patient had the typical clinical features of SPG11 and carried, in trans, the heterozygous mutations c.2358_2359delinsTT (p.Glu786_Gly787delinsAspfs*) in exon 13 and c.4868delT (p.Leu1623Tyrfs*17) in exon 28. Post-mortem delay was 48 h, explaining the presence of vacuoles in the tissue. Scale bar: 2 μm.

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