Havlicek, Steven and Kohl, Zacharias and Mishra, Himanshu K. and Prots, Iryna and Eberhardt, Esther and Denguir, Naime and Wend, Holger and Ploetz, Sonja and Boyer, Leah and Marchetto, Maria C. N. and Aigner, Stefan and Sticht, Heinrich and Groemer, Teja W. and Hehr, Ute and Lampert, Angelika and Schloetzer-Schrehardt, Ursula and Winkler, Juergen and Gage, Fred H. and Winner, Beate (2014) Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients neurons. HUMAN MOLECULAR GENETICS, 23 (10). pp. 2527-2541. ISSN 0964-6906, 1460-2083
Full text not available from this repository. (Request a copy)Abstract
The hereditary spastic paraplegias (HSPs) are a heterogeneous group of motorneuron diseases characterized by progressive spasticity and paresis of the lower limbs. Mutations in Spastic Gait 4 (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.1684CT 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 at 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 for 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEREDITARY SPASTIC PARAPLEGIA; PLURIPOTENT STEM-CELLS; STRUCTURAL BASIS; PROTEIN SPASTIN; NERVOUS-SYSTEM; MUTATIONS; TRANSPORT; PARAPARESIS; KATANIN; MODEL; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Nov 2019 13:17 |
| Last Modified: | 08 Nov 2019 13:17 |
| URI: | https://pred.uni-regensburg.de/id/eprint/10181 |
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