Spatacsin and spastizin act in the same pathway required for proper spinal motor neuron axon outgrowth in zebrafish

Martin, Elodie; Yanicostas, Constantin; Rastetter, Agnès; Naini, Seyedeh Maryam Alavi; Maouedj, Alissia; Kabashi, Edor; Rivaud-Péchoux, Sophie; Brice, Alexis; Stevanin, Giovanni; Soussi-Yanicostas, Nadia

doi:10.1016/j.nbd.2012.07.003

Cited by 45 publications

(48 citation statements)

References 38 publications

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“…Genetic approaches in zebrafish revealed that the disruption of spg11 promotes motor defects in embryos due to a significant reduction of neuromuscular junctions, the specialized synapses of the motor endplate (10,17). Both in HUES6-dNeuron and mouse cortical neuron cultures spatacsin partially overlapped with pre- (VAMP2) and postsynaptic (PSD95) markers (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Genomic screens as well as proteomic and biochemical assays demonstrated an association of spatacsin and spastizin with the adaptor protein 5 (AP5) (6,8,9). The knockdown of spg11 in zebrafish compromised the outgrowth of spinal motor axons and suggested that spatacsin may be important for the formation of neuromuscular junctions during development (10). …”

Section: Introductionmentioning

confidence: 99%

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Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia

Pérez-Brangulı́

Mishra

Prots

et al. 2014

Human Molecular Genetics

121

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Hereditary spastic paraplegias are a group of inherited motor neuron diseases characterized by progressive paraparesis and spasticity. Mutations in the spastic paraplegia gene SPG11, encoding spatacsin, cause an autosomal-recessive disease trait; however, the precise knowledge about the role of spatacsin in neurons is very limited. We for the first time analyzed the expression and function of spatacsin in human forebrain neurons derived from human pluripotent stem cells including lines from two SPG11 patients and two controls. SPG11 patients'-derived neurons exhibited downregulation of specific axonal-related genes, decreased neurite complexity and accumulation of membranous bodies within axonal processes. Altogether, these data point towards axonal pathologies in human neurons with SPG11 mutations. To further corroborate spatacsin function, we investigated human pluripotent stem cell-derived neurons and mouse cortical neurons. In these cells, spatacsin was located in axons and dendrites. It colocalized with cytoskeletal and synaptic vesicle (SV) markers and was present in synaptosomes. Knockdown of spatacsin in mouse cortical neurons evidenced that the loss of function of spatacsin leads to axonal instability by downregulation of acetylated tubulin. Finally, time-lapse assays performed in SPG11 patients'-derived neurons and spatacsin-silenced mouse neurons highlighted a reduction in the anterograde vesicle trafficking indicative of impaired axonal transport. By employing SPG11 patient-derived forebrain neurons and mouse cortical neurons, this study provides the first evidence that SPG11 is implicated in axonal maintenance and cargo trafficking. Understanding the cellular functions of spatacsin will allow deciphering mechanisms of motor cortex dysfunction in autosomal-recessive hereditary spastic paraplegia.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia

Pérez-Brangulı́

Mishra

Prots

et al. 2014

Human Molecular Genetics

121

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“…Motor axons in fish injected with strumpellin ( SPG8 ) morpholino were also shorter and had abnormal branching and impaired motility, which were rescued upon co-injection of wild-type human SPG8 mRNA but not mRNA with HSP-related variants, validating the latter as loss-of-function mutations (Valdmanis et al, 2007). Knockdown of either spatacsin ( SPG11 ) or spastizin ( SPG15 ) severely compromised branching of spinal cord motor neurons at the NMJ and caused locomotor impairment (Martin et al, 2012). Knockdown of slc33A1 [encoding Solute carrier family 33 (acetyl-CoA transporter), member 1; SPG42 ) in zebrafish embryos also caused a tail curvature phenotype and abnormal axon outgrowth from the spinal cord (Lin et al, 2008).…”

Section: Hereditary Spastic Paraplegia (Hsp)mentioning

confidence: 99%

Fishing for causes and cures of motor neuron disorders

Patten

Armstrong

Lissouba

et al. 2014

Disease Models &Amp; Mechanisms

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Motor neuron disorders (MNDs) are a clinically heterogeneous group of neurological diseases characterized by progressive degeneration of motor neurons, and share some common pathological pathways. Despite remarkable advances in our understanding of these diseases, no curative treatment for MNDs exists. To better understand the pathogenesis of MNDs and to help develop new treatments, the establishment of animal models that can be studied efficiently and thoroughly is paramount. The zebrafish (Danio rerio) is increasingly becoming a valuable model for studying human diseases and in screening for potential therapeutics. In this Review, we highlight recent progress in using zebrafish to study the pathology of the most common MNDs: spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). These studies indicate the power of zebrafish as a model to study the consequences of disease-related genes, because zebrafish homologues of human genes have conserved functions with respect to the aetiology of MNDs. Zebrafish also complement other animal models for the study of pathological mechanisms of MNDs and are particularly advantageous for the screening of compounds with therapeutic potential. We present an overview of their potential usefulness in MND drug discovery, which is just beginning and holds much promise for future therapeutic development.

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“…Intracellularly, spatacsin colocalizes with cytoskeletal and synaptic vesicle markers and is present in synaptosomes [54]. Spatacsin is believed to be important for early neuronal development, differentiation, and survival, as well as axonal transport and anterograde vesicle trafficking [32,54,55]. …”

Section: Discussionmentioning

confidence: 99%

“…Endogenous expression studies have shown similarities in the expression patterns, and intracellular and tissue localizations of spatacsin and spastizin. They partially colocalized with multiple organelles, particularly protein-trafficking vesicles, endoplasmic reticulum, and microtubules, and it was conjectured that both are involved in a common protein complex [55,56,57]. Spatacsin and spastizin co-immunoprecipitated, both from cytosol and from detergent-extracted membranes, with the four subunits of the late endosomal/lysosomal adaptor protein complex AP-5, an evolutionarily conserved member of the family of heterotetrameric adaptor proteins (AP complexes) with a stoichiometry of ∼1:1:1:1:1:1, colocalized all on a late endosomal/lysosomal compartment, and thus they are probably functionally linked to form a membrane-associated coat-like complex [58].…”

Section: Discussionmentioning

confidence: 99%

Novel Compound Heterozygous <b><i>Spatacsin</i></b> Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia

Fraidakis¹,

Brunetti

Blackstone

et al. 2016

Neurodegener Dis

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SPG11 belongs to the autosomal recessive hereditary spastic paraplegias (HSP) and presents during childhood or puberty with a complex clinical phenotype encompassing learning difficulties, ataxia, peripheral neuropathy, amyotrophy, and mental retardation. We hereby present the case of a 30-year-old female patient with complex autosomal recessive HSP with thinning of the corpus callosum (TCC) and dementia that was compound heterozygous with two novel mutations in the SPG11 gene. Sequence analysis of the SPG11 gene revealed two novel mutations in a compound heterozygous state in the index patient (c.2431C>T/p.Gln811Ter and c.6755_6756insT/p.Glu2252Aspfs*88). MRI showed abnormal TCC, white matter (WM) hyperintensities periventricularly, and the ‘ears of the lynx' sign. Diffusion tensor imaging showed a mild-to-moderate decrease in fractional anisotropy and an increase in mean diffusivity in WM compared to age-matched controls, while magnetic resonance spectroscopy showed abnormal findings in affected WM with a decrease in N-acetyl-aspartate in WM regions of interest. This is the first SPG11 kindred from the Greek population to be reported in the medical literature.

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Spatacsin and spastizin act in the same pathway required for proper spinal motor neuron axon outgrowth in zebrafish

Cited by 45 publications

References 38 publications

Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia

Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia

Fishing for causes and cures of motor neuron disorders

Novel Compound Heterozygous <b><i>Spatacsin</i></b> Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia

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