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Hereditary Spastic Paraparesis

ABSTRACT: The goal of this project is to study differentially expressed genes in patients affected by Hereditary Spastic Paraplegia (HSP) linked to mutations of the gene encoding spastin an ubiquitously expressed protein that has recently been shown to be involved in microtubule regulation and vesicle trafficking by cell culture studies. Gene profiling was done with Affymetrix U95Av2 GeneChips using the total RNA extracted from muscle biopsies of 3 SPG4-linked HSP patients. Keywords: other

ORGANISM(S): Homo sapiens

PROVIDER: GSE1300 | GEO | 2004/04/14

SECONDARY ACCESSION(S): PRJNA90225

REPOSITORIES: GEO

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Transcription profiling of human hereditary spastic paraplegia patients

Project description:The goal of this project is to study differentially expressed genes in patients affected by Hereditary Spastic Paraplegia (HSP) linked to mutations of the gene encoding spastin an ubiquitously expressed protein that has recently been shown to be involved in microtubule regulation and vesicle trafficking by cell culture studies. Gene profiling was done with Affymetrix U95Av2 GeneChips using the total RNA extracted from muscle biopsies of 3 SPG4-linked HSP patients.

2007-07-29 | E-GEOD-1300 | biostudies-arrayexpress

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Project description:Hereditary Spastic Paraplegia (HSP) leads to progressive gait disturbances with lower limb muscle weakness and spasticity. Mutations in SPG4 are a major cause of autosomal-dominant HSP. Spastin, the protein encoded by SPG4, is a microtubule-severing protein and is enriched in the distal axon of corticospinal motor neurons which degenerate in HSP patients. How SPG4 mutations cause axon degeneration in patients is not understood. Multipotent neural stem cells, accessible from patient olfactory mucosa biopsies, provided a new patient-derived cell models for HSP. Olfactory neurosphere-derived cells were obtained from cohorts of HSP patients with, and without, mutations in SPG4 and from healthy controls. Patient cells had extensive changes in expression of cell cycle-related genes and in genes associated with microtubule formation. Despite this, cell proliferation and metabolic functions of the patient cells were similar to controls. Cells with mutated SPG4 had significantly less spastin and acetylated tubulin but significantly more stathmin, a tubulin-depolymerising protein. These cells also significant deficits in the intracellular distribution of peroxisomes and mitochondria, compared to control cells. This model reveals that SPG4-HSP patient-derived neural stem/progenitors compensate for the cell cycle-related effects of reduced spastin levels in the nucleus, in part by large changes in gene expression, but failed to correct deficits in organelle trafficking. The results raise the question of whether these deficits arise directly from the loss of spastin or indirectly from the compensation. Patient-derived olfactory stem cells provide a new model for examining the neural consequences of human genetic mutations in their natural setting: at normal gene dosages against normal genetic backgrounds.

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GENOME STUDIES IN HEREDITARY SPASTIC PARAPLEGIA

Project description:GENOME STUDIES IN HEREDITARY SPASTIC PARAPLEGIA

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Project description:Hereditary Spastic Paraplegia (HSP) is a neurodegenerative disease most commonly caused by autosomal dominant mutations in the SPG4 gene encoding the microtubule severing protein spastin. We hypothesise that SPG4-HSP is attributable to reduced spastin function due to haploinsufficiency, thus therapeutic approaches which elevate levels of the wild type spastin allele may be an effective therapy. However until now, how spastin levels are regulated is largely unknown. Here, we show that the kinase HIPK2 regulates spastin protein levels in proliferating cells, in differentiated neurons and in vivo. Our work reveals that HIPK2-mediated phosphorylation of spastin at S268 inhibits spastin K48-poly-ubiquitination at K554 and prevents its neddylation-dependent proteasomal degradation. In a spastin RNAi neuronal cell model, overexpression of HIPK2, or inhibition of neddylation, restores spastin levels and rescues neurite defects. Notably, we demonstrate that spastin levels can be restored pharmacologically by inhibiting its neddylation-mediated degradation in neurons derived from a spastin mouse model of HSP and in patient derived cells, thus revealing novel therapeutic targets for the treatment of SPG4-HSP. We do not know how S268 phosphorylation prevents spastin ubiquitination at K554; we hypothesised that phosphorylation can protect spastin from polyubiquitination by impairing the recruitment of proteins belonging to ubiquitination pathway or by promoting the interactions with factors that mask spastin region necessary for efficient ubiquitination/degradation. To have insight about these hypotheses, we analysed by mass spectrometry (MS) the interactome of spastin-S268A and -S268D upon overexpression in HeLa cells.

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High-Content Screening Identifies A Small Molecule That Restores AP-4-dependent Protein Trafficking In Neuronal Models Of AP-4-Associated Hereditary Spastic Paraplegia

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Homo sapiens

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Project description:To understand the disease mechanism of SPG7 hereditary spastic paraplegia, we generated and evaluated patient and control induced pluripotent stem cell derived cortical neurons. We then performed gene expression profiling analysis using data obtained from RNA-seq.

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Project description:ER-resident membrane-shaping proteins with central reticulon homology domains (RHDs) have been associated with neurodegenerative disorders such as ARL6IP1 and FAM134B.Mutations in ARL6IP1 cause SPG61, a neurodegenerative disorder characterized by progressive leg spasticity (hereditary spastic paraplegia/HSP) in combination with loss of sensory and pain perception, thus reproducing typical symptoms of HSAN {Kurth, 2009 #8;Novarino, 2014 #28;Nizon, 2018 #162}.Our objetive was to analyse FAM134B-ARL6IP1 protein protein interactionS to underlying mechanisms, required for effective ER-remodelling and ER-phagy.

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