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targeting sequence directs spastin to the surface of lipid droplets. Depletion of the homologous spastin proteins in both flies and worms affects lipid droplet number and triacylglycerol content.
analysis of spastin's microtubule-binding properties and comparison with katanin
The spastin is a key regulator of axon regeneration, and initiation of regeneration is extremely sensitive to the spastin copy number.
Dendritic growth is regulated by Kruppel-like factor dendritic arbor reduction protein 1 (Dar1) suppressing the expression of microtubule-severing protein spastin.
spastin is essential for apical domain biogenesis during rhabdomere elongation in Drosophila photoreceptor morphogenesis
Exogenous expression of wild-type Drosophila or human spastin rescues behavioral and cellular defects in spastin null flies equivalently.
Here we identify the predicted gene product CG5977 as the Drosophila homolog of the human spastin gene, with much higher sequence similarities than any other related AAA domain protein in the fly.
D-spastin displays ATPase activity and uses energy from ATP hydrolysis to sever and disassemble microtubules; disease mutations abolish or partially interfere with these activities.
Spastin and Fidgetin are utilized to stimulate microtubule minus-end depolymerization and flux; they concentrate at centrosomes, where they catalyze the turnover of gamma-tubulin.
X ray structure; data support a model in which spastin pulls the C terminus of tubulin through its central pore, generating a mechanical force that destabilizes tubulin-tubulin interactions within the microtubule lattice
The data suggest that defective BMP and neuropilin 1 signalling may contribute to the motor phenotype in a vertebrate model of spastin depletion.
The results suggest that the spinal cord motor neuron axon outgrowth of zebrafish is regulated by the interaction between spastin and protrudin.
Simultaneous knockdown of spastin and katanin caused a more severe phenotype than did individual knockdown of either gene, suggesting that they have different but related functions in supporting axon outgrowth.
Reduced spg4 function caused dramatic defects in motor axon outgrowth without affecting the events driving the initial specification of motor neurones.
This study was conducted to elucidate the genetic etiology of patients with the pure type autosomal dominant-hereditary spastic paraparesis diagnosis. The patient group consisted of 23 individuals from 6 families in Turkey. In SPAST, 3 patients have novel c.1072G > C mutation and 2 patients have novel c.1099-1G > C mutation.
results demonstrate that, in addition to the AAA domain, the MTBD region of spastin is also involved in regulating ATPase activity, making interactions between spastin protomers more complicated than expected
The findings suggest a mechanism for neurodegeneration in hereditary spastic paraplegia whereby SPAST mutations indirectly lead to impaired peroxisome transport and oxidative stress.
study to explore the novel SPAST splice site donor variant, c.1004+3A>C in spastic paraplegia type 4; Exon 6 is skipped out by the variant, leading to premature termination of translation, p.Gly290Trpfs*5; measurement of SPAST transcripts in lymphocytes demonstrated reduction through nonsense-mediated mRNA decay
Two novel mutations in gene SPG4 in patients with autosomal dominant spastic paraplegia
The N184X mutation triggers the reinitiation of translation at a third start codon in SPAST, resulting in synthesis of a novel M187 spastin isoform that is able to sever microtubules.
Our data reveal a high rate of complex cases (25%), with psychiatric disorders among the most common comorbidity (10% of all SPASTpatients). Further, we identify a genotype-phenotype correlation between patients carrying loss-of-function mutations in SPAST and the presence of psychiatric disorders.
Variants in SPAST and KIF5A were the most common causes of autosomal dominant hereditary spastic paraplegia in Greece.
Two distinct Alu insertion-associated deletions in the SPAST gene cause hereditary spastic paraplegia type SPG4.
The data of this study confirmed the genetic heterogeneity of childhood-onset pure HSP, with SPG4/SPAST and SPG3A/ATL1 being the most frequent forms.
We report the first genetic study of uncomplicated HSP patients from the Czech Republic. We found broad mutation spectrum in 13 from the 17 coding exons and adjacent regions of the SPAST gene. We detected 21 novel presumably pathogenic mutations. The high frequency of SPAST mutations was found only in familial patients.
This study demonstrted that the most frequently affected gene was SPAST with pathogenic or likely pathogenic mutations in hereditary spastic paraplegia.
This study demonstrated that SPAST gene mutation associated with hereditary spastic paraplegias in group of Polish patients
We identified two novel mutations and two previously reported mutations in SPAST and ATL1, respectively. The family with the ATL1 c.1204T>G mutation exhibited male-lethality, female infancy-onset, and pseudo- X-linked dominant transmission
Using human-engineered and differentially modified microtubules study finds that glutamylation is the main regulator of the hereditary spastic paraplegia microtubule severing enzyme spastin.
Patients with deletions of exons in the SPAST gene showed pure hereditary spastic paraplegia.
Novel SPAST pathogenic variants were identified in Korean patients with hereditary spastic paraplegia.
The coexistence of mutations in SPAST and FSHD was confirmed in our proband and in two siblings
The spastin as a microtubule-severing protein was an important mechanistic breakthrough, it seems certain that insufficient microtubule severing alone is not an adequate explanation for HSP-SPG4.
SPAST mutations are common in Chinese patients with pure hereditary spastic paraplegia
two isoforms of spastin harboring the same missense mutation bind and bundle different subsets of microtubules.
Spastin regulates VAMP7-containing vesicles trafficking in cortical neurons.
Axon branch loss at the developing mouse neuromuscular junction is mediated by branch-specific microtubule severing, mediated by the microtubule-severing enzyme spastin.
Spastin is recruited by microtubules polyglutamylation, induced by Tau missorting triggered translocalization of TTLL6 (Tubulin-Tyrosine-Ligase-Like-6) into dendrites
early and marked impairment of microtubule dynamics all along the axons of spastin-deficient cortical neurons, which is likely to be responsible for the occurrence of axonal swellings and cargo stalling
we aimed to identify the critical promoter regions of SPG4 gene and effects of Elk1 on SPG4 gene expression
Sequence analysis of the SPG4 (spastin) gene identified a novel 1593 C > T (GLN490Stop) mutation in hereditary spastic paraplegia with cerebellar ataxia.
two modes by which microtubule severing occurs during axonal branch formation, based on the concentration of spastin at branch sites and on local detachment from microtubules of molecules such as tau that regulate the severing properties of P60-katanin
These results strongly support a direct role for defective axonal transport in the pathogenesis of HSP because of spastin mutation.
A defective SPAST gene in cattle is associated with a recessive, congenital neurodegenerative disease, which is characterized by pathological changes of the myelin sheaths in the spinal cord.
This gene encodes a member of the AAA (ATPases associated with a variety of cellular activities) protein family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. The encoded ATPase may be involved in the assembly or function of nuclear protein complexes. Two transcript variants encoding distinct isoforms have been identified for this gene. Other alternative splice variants have been described but their full length sequences have not been determined. Mutations associated with this gene cause the most frequent form of autosomal dominant spastic paraplegia 4.
, spastic paraplegia 4 (autosomal dominant; spastin)
, spastic paraplegia 4 protein
, spastic paraplegia 4 homolog
, spastic paraplegia 4 (autosomal dominant
, neuronal spastin