Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration

Boutry, Maxime; Branchu, Julien; Lustremant, Céline; Pujol, Claire; Pernelle, Julie; Matusiak, Raphaël; Seyer, Alexandre; Poirel, Marion; Chu‐Van, Emeline; Pierga, Alexandre; Dobrenis, Kostantin; Puech, Jean; Caillaud, Catherine; Dürr, Alexandra; Brice, Alexis; Colsch, Benoît; Mochel, Fanny; Hachimi, Khalid Hamid El; Stevanin, Giovanni; Darios, Frédéric

doi:10.1016/j.celrep.2018.05.098

Cited by 65 publications

(78 citation statements)

References 33 publications

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“…2C). The scission of lysosome tubules requires dynamin (10), a binding partner of spatacsin (12). The inhibition of dynamin by dynasore increased the proportion of cholesterol colocalized with late endosomes/lysosomes in control, but not in Spg11 -/fibroblasts ( Fig.…”

Section: Results: the Formation Of Tubules On Lysosomes Contributes Tmentioning

confidence: 93%

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Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis

Boutry

Pierga

Matusiak

et al. 2019

Preprint

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Mutations in SPG11, leading to loss of spatacsin function, impair the formation of membrane tubules in lysosomes and cause the accumulation of lipids in lysosome compartment. However, the full nature of lipids accumulating in lysosomes and the physiological consequences of such accumulation are not known. Here we show that loss of spatacsin, but also downregulation of clathrin, inhibited the formation of tubules on late endosomes/lysosomes and prevented the clearance of cholesterol from this subcellular compartment. Using spatacsin-deficient cells, we evaluated the consequences of impaired cholesterol clearance from late endosomes/lysosomes. The accumulation of cholesterol in late endosomes/lysosomes led to lower cholesterol levels in the plasma membrane, enhancing the entry of extracellular calcium by store-operated calcium entry and increasing resting cytosolic calcium levels.Higher cytosolic calcium levels promoted the nuclear translocation of the master regulator of lysosomes TFEB. Downregulation of TFEB or decrease in resting calcium levels in absence of spatacsin partially corrected the formation of tubules and the accumulation of cholesterol in lysosomes, suggesting that spatacsin could be indirectly implicated in the formation of tubules. Our work reveals a homeostatic balance between cholesterol trafficking and cytosolic calcium levels and shows that loss of spatacsin impairs this homeostatic equilibrium.

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Section: Results: the Formation Of Tubules On Lysosomes Contributes Tmentioning

confidence: 93%

“…The loss of spatacsin has been shown to impair lysosomal function (11,12). We therefore analyzed the localization of lysosomes in control and spatacsin-deficient (Spg11 -/-) fibroblasts by LAMP1 immunostaining.…”

Section: Results: the Formation Of Tubules On Lysosomes Contributes Tmentioning

confidence: 99%

Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis

Boutry

Pierga

Matusiak

et al. 2019

Preprint

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“…Krabbe disease and metachromatic leukodystrophy belong to the group of lysosomal storage disorders. However, accumulation of some glycosphingolipids in lysosomes has also been observed in SPG11 models of HSP (Boutry et al, 2018) that is not classically considered as a lysosomal storage disorder. Accumulation of gangliosides in SPG11 was likely not due to impaired function of ganglioside-degrading enzymes, suggesting that the accumulation of gangliosides has another cause.…”

Section: Sphingolipid Degradationmentioning

confidence: 97%

“…SPG11 is due to the loss of function of spatacsin, a protein that has been implicated in the autophagic lysosome reformation, a mechanism allowing formation of tubule in autolysosomes at the end of the autophagy process to recycle lysosome membrane . It has been proposed that inhibition of the tubulation in absence of spatacsin could lead to accumulation of gangliosides in lysosomes, which could contribute to the motor dysfunction observed in the mouse model (Branchu et al, 2017;Boutry et al, 2018). Some SPG11 patients are diagnosed as cases of amyotrophic lateral sclerosis or Charcot-Marie tooth disease (Orlacchio et al, 2010;Montecchiani et al, 2016).…”

Section: Sphingolipid Degradationmentioning

confidence: 99%

Lipids in the Physiopathology of Hereditary Spastic Paraplegias

2020

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Hereditary spastic paraplegias (HSP) are a group of neurodegenerative diseases sharing spasticity in lower limbs as common symptom. There is a large clinical variability in the presentation of patients, partly underlined by the large genetic heterogeneity, with more than 60 genes responsible for HSP. Despite this large heterogeneity, the proteins with known function are supposed to be involved in a limited number of cellular compartments such as shaping of the endoplasmic reticulum or endolysosomal function. Yet, it is difficult to understand why alteration of such different cellular compartments can lead to degeneration of the axons of cortical motor neurons. A common feature that has emerged over the last decade is the alteration of lipid metabolism in this group of pathologies. This was first revealed by the identification of mutations in genes encoding proteins that have or are supposed to have enzymatic activities on lipid substrates. However, it also appears that mutations in genes affecting endoplasmic reticulum, mitochondria, or endolysosome function can lead to changes in lipid distribution or metabolism. The aim of this review is to discuss the role of lipid metabolism alterations in the physiopathology of HSP, to evaluate how such alterations contribute to neurodegenerative phenotypes, and to understand how this knowledge can help develop therapeutic strategy for HSP.

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“…In the brain of patients with a mutation in SPG11 gene and in Spg11 knockout mice a lipid accumulation especially of GM2, GM3, GD2, and GD3 as well as an accumulation of autophagy markers (e.g., p62) were observed in the endolysosomes [171,172]. Unfortunately, no studies exist about the lipid content of AP 5 or SPG15 deficient cells or tissue.…”

Section: Hereditary Spastic Paraplegia (Hsp)mentioning

confidence: 99%

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Breiden

Sandhoff

2020

IJMS

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Gangliosidoses are caused by monogenic defects of a specific hydrolase or an ancillary sphingolipid activator protein essential for a specific step in the catabolism of gangliosides. Such defects in lysosomal function cause a primary accumulation of multiple undegradable gangliosides and glycosphingolipids. In reality, however, predominantly small gangliosides also accumulate in many lysosomal diseases as secondary storage material without any known defect in their catabolic pathway. In recent reconstitution experiments, we identified primary storage materials like sphingomyelin, cholesterol, lysosphingolipids, and chondroitin sulfate as strong inhibitors of sphingolipid activator proteins (like GM2 activator protein, saposin A and B), essential for the catabolism of many gangliosides and glycosphingolipids, as well as inhibitors of specific catabolic steps in lysosomal ganglioside catabolism and cholesterol turnover. In particular, they trigger a secondary accumulation of ganglioside GM2, glucosylceramide and cholesterol in Niemann-Pick disease type A and B, and of GM2 and glucosylceramide in Niemann-Pick disease type C. Chondroitin sulfate effectively inhibits GM2 catabolism in mucopolysaccharidoses like Hurler, Hunter, Sanfilippo, and Sly syndrome and causes a secondary neuronal ganglioside GM2 accumulation, triggering neurodegeneration. Secondary ganglioside and lipid accumulation is furthermore known in many more lysosomal storage diseases, so far without known molecular basis.

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Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration

Cited by 65 publications

References 33 publications

Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis

Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis

Lipids in the Physiopathology of Hereditary Spastic Paraplegias

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

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