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

Pérez-Brangulı́, Francesc; Mishra, Himanshu; Prots, Iryna; Havlicek, Steven; Kohl, Zacharias; Saul, Domenica; Rummel, Christine; Dorca-Arévalo, Jonatan; Regensburger, Martin; Graef, Daniela; Sock, Elisabeth; Blasi, Juan; Groemer, Teja W.; Schlötzer‐Schrehardt, Ursula; Winkler, Jürgen; Winner, Beate

doi:10.1093/hmg/ddu200

Cited by 90 publications

(134 citation statements)

References 36 publications

(66 reference statements)

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“…Lysates were cleared by centrifugation at 11,000 g for 10 minutes at 4ºC, and immunoblot analysis was performed using the protocol described earlier 12, 19…”

Section: Methodsmentioning

confidence: 99%

GSK3ß‐dependent dysregulation of neurodevelopment in SPG11‐patient induced pluripotent stem cell model

Mishra

Prots

Havlicek

et al. 2016

Annals of Neurology

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ObjectiveMutations in the spastic paraplegia gene 11 (SPG11), encoding spatacsin, cause the most frequent form of autosomal‐recessive complex hereditary spastic paraplegia (HSP) and juvenile‐onset amyotrophic lateral sclerosis (ALS5). When SPG11 is mutated, patients frequently present with spastic paraparesis, a thin corpus callosum, and cognitive impairment. We previously delineated a neurodegenerative phenotype in neurons of these patients. In the current study, we recapitulated early developmental phenotypes of SPG11 and outlined their cellular and molecular mechanisms in patient‐specific induced pluripotent stem cell (iPSC)‐derived cortical neural progenitor cells (NPCs).MethodsWe generated and characterized iPSC‐derived NPCs and neurons from 3 SPG11 patients and 2 age‐matched controls.ResultsGene expression profiling of SPG11‐NPCs revealed widespread transcriptional alterations in neurodevelopmental pathways. These include changes in cell‐cycle, neurogenesis, cortical development pathways, in addition to autophagic deficits. More important, the GSK3ß‐signaling pathway was found to be dysregulated in SPG11‐NPCs. Impaired proliferation of SPG11‐NPCs resulted in a significant diminution in the number of neural cells. The decrease in mitotically active SPG11‐NPCs was rescued by GSK3 modulation.InterpretationThis iPSC‐derived NPC model provides the first evidence for an early neurodevelopmental phenotype in SPG11, with GSK3ß as a potential novel target to reverse the disease phenotype. Ann Neurol 2016;79:826–840

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“…Lysates were cleared by centrifugation at 11,000 g for 10 minutes at 4ºC, and immunoblot analysis was performed using the protocol described earlier 12, 19…”

Section: Methodsmentioning

confidence: 99%

GSK3ß‐dependent dysregulation of neurodevelopment in SPG11‐patient induced pluripotent stem cell model

Mishra

Prots

Havlicek

et al. 2016

Annals of Neurology

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“…Transcript expression analysis of spatacsin demonstrated ubiquitous distribution in the nervous system, with high expression in embryos, and in cortical and spinal motor neurons as well as in the retina [8,21,23]. 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%

“…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%

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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“…48 Another group analyzed the expression and function of the spatacsin protein (mutated in SPG11) in human forebrain neurons derived from human iPSCs, including patient and control lines. 49 The SPG11 patient-derived neurons exhibited downregulation of specific axonal-related genes, a decrease in neurite complexity, and an accumulation of membranous bodies within axonal processes. These findings pointed toward axonal dysfunction in human neurons with SPG11 mutations.…”

Section: Neurons Derived From Induced Pluripotent Stem Cellsmentioning

confidence: 97%

An Update on the Hereditary Spastic Paraplegias: New Genes and New Disease Models

Kumar

Blair

Sue

2015

Movement Disord Clin Pract

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Aims: The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by spasticity in the lower limbs. We provide an overview of HSP with an emphasis on recent developments. Methods: A PubMed search using the term "hereditary spastic paraplegia" and "hereditary spastic paraparesis" was conducted for a period from January 2012 to January 2015. We discuss and critique the major studies in the field over this 36-month period. Results: A total of 346 publications were identified, of which 47 were selected for review. We provide an update of the common forms of HSP and include patient videos. We also discuss how next-generation sequencing (NGS) has led to the accelerated discovery of new HSP genes, including B4GALNT1, DDHD1, C19orf12, GBA2, TECPR2, DDHD2, C12orf65, REEP2, and IBA57. Moreover, a single study alone identified 18 previously unknown putative HSP genes and created a model for the protein interactions of HSP, called the "HSPome." Many of the newly reported genes cause rare, complicated, autosomal recessive forms of HSP. NGS also has important clinical applications by facilitating the molecular diagnosis of HSP. Furthermore, common genetic forms of HSP have been studied using new disease models, such as neurons derived from induced pluripotent stem cells. These models have been used to elucidate important disease mechanisms and have served as platforms to screen for candidate drug compounds. Conclusion: The field of HSP research has been progressing at a rapid pace. The challenge remains in translating these advances into new targeted disease therapies.The term "hereditary spastic paraplegia" (HSP) is applied to a group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness in the lower limbs.There is marked genetic heterogeneity in HSP, with at least 55 genes and 72 loci identified thus far. The mode of inheritance can be autosomal dominant, autosomal recessive, X-linked, or maternal.

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

Cited by 90 publications

References 36 publications

GSK3ß‐dependent dysregulation of neurodevelopment in SPG11‐patient induced pluripotent stem cell model

GSK3ß‐dependent dysregulation of neurodevelopment in SPG11‐patient induced pluripotent stem cell model

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

An Update on the Hereditary Spastic Paraplegias: New Genes and New Disease Models

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