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.

Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis

“…Our data support the hypothesis that the loss of spatacsin leads to similar impairment of cholesterol and calcium homeostasis both in non-neuronal cells and in neurons. Hereditary spastic paraplegia SPG11 is characterized by neuronal death in various brain regions (4,36). The persistent deregulation of cholesterol distribution could lead to a slight modification of calcium homeostasis.…”

“…Calcium plays a central role in cellular physiology and neuronal transmission (37) and a persistent change in cytosolic calcium levels could explain the behavioral alterations that were observed in Spg11 -/mice long before neurodegeneration occurred (4). Alternatively, alteration in calcium homeostasis in absence of spatacsin, could also contribute, in the long term, to neurodegeneration (38).…”

“…Spg11 -/mice were described previously (4). Mouse embryonic fibroblasts (MEFs) were prepared using E14.5 embryos obtained from the breeding of heterozygous mice.…”

“…Most mutations are truncating mutations, suggesting that the symptoms are due to loss of function of the SPG11 product, spatacsin (3). Accordingly, knockout of Spg11 in the mouse reproduces the main motor and cognitive symptoms observed in patients (4). Studies in SPG11 patient fibroblasts and in Spg11 knockout mice suggested that loss of spatacsin led to impaired function of lysosomes (4)(5)(6).…”

“…Accordingly, knockout of Spg11 in the mouse reproduces the main motor and cognitive symptoms observed in patients (4). Studies in SPG11 patient fibroblasts and in Spg11 knockout mice suggested that loss of spatacsin led to impaired function of lysosomes (4)(5)(6). Lysosomes are organelles containing hydrolytic enzymes that notably fuse with endosomes or autophagosomes to allow degradation of their content.…”