Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis

Boutry, Maxime; Pierga, Alexandre; Matusiak, Raphaël; Branchu, Julien; Houllegatte, M.; Ibrahim, Yoan; Balse, Elise; Hachimi, Khalid-Hamid El; Brice, Alexis; Stevanin, Giovanni; Darios, Frédéric

doi:10.1038/s42003-019-0615-z

Cited by 35 publications

(41 citation statements)

References 58 publications

(89 reference statements)

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“…In mice, loss of Spg11 led to early cognitive and motor deficits, consistent with the symptoms observed in the majority of patients with mutations in the SPG11 gene (Branchu et al, 2017). Loss of spatacsin impairs the formation of membrane tubules in lysosomes and cause lysosomal lipid accumulation altering the homeostatic equilibrium between cholesterol trafficking and cytosolic calcium levels (Boutry et al, 2019b). Downregulation of spg11 in zebrafish resulted in abnormal axon outgrowth (Martin et al, 2012) and a range of developmental defects (Table 1) and CNS abnormalities.…”

Section: Spg11supporting

confidence: 60%

“…To date, it clearly emerged that HSP, HA, ASS, and other neurological disorders are part of a continuum of overlapping clinical conditions. For instance, the clinical overlap of HSP with HA or intellectual/ developmental disability is not new and so it is the overlap with the mechanisms involved in more common neurological conditions including amyotrophic lateral sclerosis, multiple sclerosis, Parkinson disease, and dementias (Patten et al, 2014;Parodi et al, 2017;Boutry et al, 2019b;Shribman et al, 2019). Since HSP and ASS are a group of disorders characterized by high genetic diversity, researchers have widely exploited the zebrafish as an in vivo model system of these pathologies.…”

Section: Conclusion and Future Applicationsmentioning

confidence: 99%

“…Pathologically, the neurodegeneration characterizing HSP is a progressive distal axonopathy of the corticospinal tract and posterior columns in the spinal cord (Salinas et al, 2008;Parodi et al, 2017;Synofzik and Schüle, 2017), in other words a dying-back degeneration that progresses from the distal end of the axons (Boutry et al, 2019b). The axons involved in this degeneration are commonly characterized by a unique, highly polarized architecture (Boutry et al, 2019b). This evidence, together with the discovery that genes involved in axonal transport, intracellular trafficking, and mitochondrial functions are implicated in HSP, suggests that abnormalities in these processes play a role in HSP.…”

Section: Introductionmentioning

confidence: 99%

“…However, in complicated HSP, the fact that the neurodegeneration can also involve the cerebellum, cerebral cortex, corpus callosum, and basal ganglia (Hensiek et al, 2015) suggests the involvement of other pathological mechanisms (Boutry et al, 2019b). The identification of other HSP causative genes, together with the discovery of the function of the related proteins, has made it possible to hypothesize at least 10 functional "modes of action" that could play a role in HSP pathogenesis, and also appear to be involved in other neurological disorders: namely, dysfunction of axonal transport, abnormal membrane trafficking and organelle shaping, abnormal endosome membrane trafficking and vesicle formation, oxidative stress, abnormal lipid metabolism, abnormal DNA repair, dysregulation of myelination, autophagy, impairment of axonal development, and abnormal cellular signaling in protein morphogenesis (Lo Giudice et al, 2014;Boutry et al, 2019b). The various forms of HSP, as well as the groups of similar neurodegenerative diseases, such as hereditary ataxia (HA), spinocerebellar ataxia (SCA), autosomal-recessive spinocerebellar ataxia (SCAR), and spastic paraplegia, can be due to mutations in either the spastic paraplegia gene (SPG) or the spastic ataxia genes (SPAX).…”

Section: Introductionmentioning

confidence: 99%

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Swimming in Deep Water: Zebrafish Modeling of Complicated Forms of Hereditary Spastic Paraplegia and Spastic Ataxia

et al. 2019

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Hereditary spastic paraplegia (HSP) and hereditary ataxia (HA) are two groups of disorders characterized, respectively, by progressive dysfunction or degeneration of the pyramidal tracts (HSP) and of the Purkinje cells and spinocerebellar tracts (HA). Although HSP and HA are generally shown to have distinct clinical-genetic profiles, in several cases the clinical presentation, the causative genes, and the cellular pathways and mechanisms involved overlap between the two forms. Genetic analyses in humans in combination with in vitro and in vivo studies using model systems have greatly expanded our knowledge of spinocerebellar degenerative disorders. In this review, we focus on the zebrafish (Danio rerio), a vertebrate model widely used in biomedical research since its overall nervous system organization is similar to that of humans. A critical analysis of the literature suggests that zebrafish could serve as a powerful experimental tool for molecular and genetic dissection of both HA and HSP. The zebrafish, found to be very useful for demonstrating the causal relationship between defect and mutation, also offers a useful platform to exploit for the development of therapies.

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Section: Spg11supporting

confidence: 60%

Section: Conclusion and Future Applicationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Swimming in Deep Water: Zebrafish Modeling of Complicated Forms of Hereditary Spastic Paraplegia and Spastic Ataxia

et al. 2019

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“…Recently, it was shown that the formation of tubules on lysosomes mediated by spatacsin allows the recycling of cholesterol from lysosomes. Loss of spatacsin led to an accumulation of cholesterol in lysosomes and decreased cholesterol content in plasma membrane (Boutry et al, 2019b), which could affect membrane properties and function. This highlights that impaired cholesterol trafficking and not only cholesterol overload in lysosomes could contribute to the pathology.…”

Section: Alteration Of Cholesterol Synthesis or Trafficking In Hspmentioning

confidence: 99%

Lipids in the Physiopathology of Hereditary Spastic Paraplegias

2020

Self Cite

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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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Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients

Krumm,

Pozner,

Zagha

et al. 2024

Acta Neuropathol

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Biallelic loss of SPG11 function constitutes the most frequent cause of complicated autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callosum, resulting in progressive multisystem neurodegeneration. While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11–HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11–HSP, including examination of three human postmortem brain donations, immunophenotyping of patients’ peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL). We delineate a previously unknown role of innate immunity in SPG11–HSP. Neuropathological analysis of SPG11–HSP patient brain tissue revealed profound microgliosis in areas of neurodegeneration, downregulation of homeostatic microglial markers and cell-intrinsic accumulation of lipids and lipofuscin in IBA1+ cells. In a larger cohort of SPG11–HSP patients, the ratio of peripheral classical and intermediate monocytes was increased, along with increased serum levels of IL-6 that correlated with disease severity. Stimulation of patient-specific iMGLs with IFNγ led to increased phagocytic activity compared to control iMGL as well as increased upregulation and release of proinflammatory cytokines and chemokines, such as CXCL10. On a molecular basis, we identified increased STAT1 phosphorylation as mechanism connecting IFNγ-mediated immune hyperactivation and SPG11 loss of function. STAT1 expression was increased both in human postmortem brain tissue and in an Spg11–/– mouse model. Application of an STAT1 inhibitor decreased CXCL10 production in SPG11 iMGL and rescued their toxic effect on SPG11 neurons. Our data establish neuroinflammation as a novel disease mechanism in SPG11–HSP patients and constitute the first description of myeloid cell/ microglia activation in human SPG11–HSP. IFNγ/ STAT1-mediated neurotoxic effects of hyperreactive microglia upon SPG11 loss of function indicate that immunomodulation strategies may slow down disease progression.

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Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis

Cited by 35 publications

References 58 publications

Swimming in Deep Water: Zebrafish Modeling of Complicated Forms of Hereditary Spastic Paraplegia and Spastic Ataxia

Swimming in Deep Water: Zebrafish Modeling of Complicated Forms of Hereditary Spastic Paraplegia and Spastic Ataxia

Lipids in the Physiopathology of Hereditary Spastic Paraplegias

Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients

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