Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Modeling Spastic Paraplegia 4 using Human Corticospinal Motor Neuron enriched Cortical Organoids Uncovers Genotype–Phenotype Distinctions and HDAC6-Targetable Pathology

ABSTRACT: Spastic Paraplegia 4 (SPG4), the most common form of Hereditary Spastic Paraplegia, causes progressive gait deficiency due to corticospinal tract degeneration. SPG4 results from mutations in the SPAST gene, which encodes spastin, a microtubule-severing AAA-ATPase. To dissect genotype–phenotype relationships, we generated isogenic human induced pluripotent stem cell lines carrying either a SPAST missense (SPASTWT/C448Y) or truncation (SPASTWT/S245X) mutation and differentiated them into motor cortical organoids. These models revealed mutation-specific patterns of aberrant neuronal activity, microtubule hypoacetylation and axonal degeneration. We identified mutant M1-spastin-induced hyperactivation of histone deacetylase 6 (HDAC6), a major tubulin deacetylase as the key pathogenic culprit. Pharmacological inhibition of HDAC6 with Tubastatin A restored microtubule acetylation and rescued axonal degeneration in organoids, with corresponding improvements in corticospinal tract integrity and gait defects in SPG4 transgenic mice. Our study uncovers HDAC6 hyperactivation as a targetable mechanism for SPG4 and verifies human organoids as a platform for therapeutic discovery.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316534 | GEO | 2026/01/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A patient-derived neural stem cell model for hereditary spastic paraplegia

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.

2012-12-20 | E-TABM-1180 | biostudies-arrayexpress

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

Hyperactivity of the non-canonical inflammasome promotes neuroinflammation in Hereditary Spastic Paraplegia type SPG11 and SPG48

Project description:Hereditary spastic paraplegia (HSP) is characterized by a spastic gait disorder due to degeneration of corticospinal axons. The genetics of this disease is highly heterogeneous with more than 80 different genes involved which are denoted as SPGs. Variants in SPG11 are responsible for the most common autosomal recessive HSP also known as SPG11. Its gene product Spatacsin interacts with the adaptor protein 5 complex (AP5), which is presumed to function in membrane trafficking, but pathways and cargoes are largely elusive. Because neurodegeneration in SPG11 is accompanied by marked neuroinflammation, we considered that Spatacsin may play a cell-autonomous role in proinflammatory cell types. Thus, its disruption may perpetuate neuroinflammation and disease progression. Here, we show that Spg11 KO mice display a more pronounced activation of microglia upon systemic challenge with Lipopolysaccharide (LPS). Our subsequent studies in primary microglia and bone marrow derived macrophages (BMDMs) demonstrate that the activation of the non-canonical inflammasome results in a much stronger inflammatory response in Spg11 KO cells, while the canonical pathway is unaffected. These findings are also observed in monocyte-derived macrophages isolated from patients carrying loss-of-function variants in SPG11. In vivo, LPS triggers a much stronger inflammatory response and leads to drastically increased lethality in Spg11 KO mice. Mass spectrometry of activated BMDMs unveils a massive downregulation of AP5 subunits upon disruption of Spg11. Notably, the disruption of its ζ-subunit Ap5z1, which is associated with SPG48, also sensitizes the non-canonical inflammasome. Altogether, our findings provide novel insights into the pathophysiology of SPG11 and SPG48 and suggest that patients with loss-of-function variants in SPG11 or SPG48 may be prone for severe systemic inflammation and organ dysfunction upon infection with Gram-negative bacteria.

2025-11-11 | PXD065699 | Pride

Project description:hereditary spastic paraplegia

| PRJNA699100 | ENA

Hereditary Spastic Paraparesis

2004-04-14 | GSE1300 | GEO

KIF1A Hereditary Spastic Paraparesis

Project description:<p>The study involves a single consanguineous Palestinian family with Hereditary Spastic Paraparesis (HSP). The affected individuals suffer from spasticity of the lower limbs and abnormal gait. Using exome sequencing and homozygosity mapping, our analysis implicated the causative mutation in the motor domain of KIF1A, a gene that functions in anterograde axonal transportation.</p>

| phs000359 | dbGaP

Gene expression profile for L1CAM knockdown in esophageal squamous carcinoma cell

Project description:The protein encoded by this gene is an axonal glycoprotein belonging to the immunoglobulin supergene family. The ectodomain, consisting of several immunoglobulin-like domains and fibronectin-like repeats (type III), is linked via a single transmembrane sequence to a conserved cytoplasmic domain. This cell adhesion molecule plays an important role in nervous system development, including neuronal migration and differentiation. Mutations in the gene cause X-linked neurological syndromes known as CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus). Alternative splicing of this gene results in multiple transcript variants, some of which include an alternate exon that is considered to be specific to neurons.

2016-09-01 | GSE86268 | GEO

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.

2023-05-30 | GSE233258 | GEO

Homo sapiens

Project description:GENOME STUDIES IN HEREDITARY SPASTIC PARAPLEGIA

| PRJNA314000 | ENA

GENOME STUDIES IN HEREDITARY SPASTIC PARAPLEGIA

Project description:GENOME STUDIES IN HEREDITARY SPASTIC PARAPLEGIA

| PRJNA313999 | ENA