Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Among the four loci causing AD-HSP identified so far, the SPG4 locus at chromosome 2p2-1p22 has been shown to account for 40-50% of all AD-HSP families. Using a positional cloning strategy based on obtaining sequence of the entire SPG4 interval, we identified a candidate gene encoding a new member of the AAA protein family, which we named spastin. Sequence analysis of this gene in seven SPG4-linked pedigrees revealed several DNA modifications, including missense, nonsense and splice-site mutations. Both SPG4 and its mouse orthologue were shown to be expressed early and ubiquitously in fetal and adult tissues. The sequence homologies and putative subcellular localization of spastin suggest that this ATPase is involved in the assembly or function of nuclear protein complexes.
"The frequency of SPG4 is higher and the incidence of SPG3A is lower in Koreans than in other ethnic groups,9,10,11,12,13 which might be attributable to an ethnic difference in the genetic background of Korean patients with HSP. However, this needs to be confirmed in a larger series. "
[Show abstract][Hide abstract] ABSTRACT: Background and Purpose
Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders that are characterized by progressive spasticity and weakness of the lower limbs. Mutations in the spastin gene (SPAST) are the most common causes of HSP, accounting for 40-67% of autosomal dominant HSP (AD-HSP) and 12-18% of sporadic cases. Mutations in the atlastin-1 gene (ATL1) and receptor expression-enhancing protein 1 gene (REEP1) are the second and third most common causes of AD-HSP, respectively.
Direct sequence analysis was used to screen mutations in SPAST, ATL1, and REEP1 in 27 unrelated Korean patients with pure and complicated HSP. Multiplex ligation-dependent probe amplification was also performed to detect copy-number variations of the three genes.
Ten different SPAST mutations were identified in 11 probands, of which the following 6 were novel: c.760A>T, c.131C>A, c.1351_1353delAGA, c.376_377dupTA, c.1114A>G, and c.1372A>C. Most patients with SPAST mutations had AD-HSP (10/11, 91%), and the frequency of SPAST mutations accounted for 66.7% (10/15) of the AD-HSP patients. No significant correlation was found between the presence of the SPAST mutation and any of the various clinical parameters of pure HSP. No ATL1 and REEP1 mutations were detected.
We conclude that SPAST mutations are responsible for most Korean cases of genetically confirmed AD-HSP. Our observation of the absence of ATL1 and REEP1 mutations needs to be confirmed in larger series.
"It is assumed, that adenosine triphosphate (ATP)-bound spastin forms hexameric rings with a central core, and it has been proposed that the positively charged central pore of spastin is able to pull the negatively charged C-terminal tail of tubulin and generate breaks in the microtubule (10,11). The spastin domains involved in microtubule severing are the microtubule-binding domain (residues 270–328) and the AAA domain (residues 342–599) (5). "
[Show abstract][Hide abstract] ABSTRACT: The hereditary spastic paraplegias (HSP) are a heterogeneous group of motorneuron diseases characterized by progressive spasticity and paresis of the lower limbs. Mutations in SPG4, encoding Spastin, are the most frequent cause of HSP. To understand how mutations in SPG4 affect human neurons, we generated human induced pluripotent stem cells (hiPSCs) from fibroblasts of two patients carrying a c.1684C>T nonsense mutation, and from two controls. These SPG4 and control hiPSCs were able to differentiate into neurons and glia at comparable efficiency.All known Spastin isoforms were reduced in SPG4 neuronal cells. The complexity of SPG4 neurites was decreased, which was paralleled by an imbalance of axonal transport with less retrograde movement. Prominent neurite swellings with disrupted microtubules were present in SPG4 neurons on an ultrastructural level. While some of these swellings contain acetylated and detyrosinated tubulin, these tubulin modifications were unchanged in total cell lysates of SPG4 neurons. Upregulation of another microtubule severing protein, p60 Katanin, may partially compensate microtubuli dynamics in SPG4 neurons.Overexpression of the M1 or M87 Spastin isoforms restored neurite length, branching, numbers of primary neurites and reduced swellings in SPG4 neuronal cells. We conclude that neurite complexity and maintenance in HSP patient-derived neurons are critically sensitive to Spastin gene dosage. Our data show that elevation of single Spastin isoform levels is sufficient to restore neurite complexity and reduce neurite swellings in patient cells. Furthermore, our human model offers an ideal platform for pharmacological screenings with the goal to restore physiological Spastin levels in SPG4 patients.
Human Molecular Genetics 12/2013; 23(10). DOI:10.1093/hmg/ddt644 · 6.39 Impact Factor
"Rachel Allison, 1,3 Jennifer H. Lumb, 1,3 Coralie Fassier, 4,5,6 James W. Connell, 1,3 Daniel Ten Martin, 4,5,6 Matthew N.J. Seaman, 2,3 Jamilé Hazan, 4,5,6 and Evan Reid 1,3 in MTs (Hazan et al., 1999; Blackstone et al., 2011; Lumb et al., 2012 "
[Show abstract][Hide abstract] ABSTRACT: Mechanisms coordinating endosomal degradation and recycling are poorly understood, as are the cellular roles of microtubule (MT) severing. We show that cells lacking the MT-severing protein spastin had increased tubulation of and defective receptor sorting through endosomal tubular recycling compartments. Spastin required the ability to sever MTs and to interact with ESCRT-III (a complex controlling cargo degradation) proteins to regulate endosomal tubulation. Cells lacking IST1 (increased sodium tolerance 1), an endosomal sorting complex required for transport (ESCRT) component to which spastin binds, also had increased endosomal tubulation. Our results suggest that inclusion of IST1 into the ESCRT complex allows recruitment of spastin to promote fission of recycling tubules from the endosome. Thus, we reveal a novel cellular role for MT severing and identify a mechanism by which endosomal recycling can be coordinated with the degradative machinery. Spastin is mutated in the axonopathy hereditary spastic paraplegia. Zebrafish spinal motor axons depleted of spastin or IST1 also had abnormal endosomal tubulation, so we propose this phenotype is important for axonal degeneration.
The Journal of Cell Biology 07/2013; 202(3). DOI:10.1083/jcb.201211045 · 9.83 Impact Factor
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