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Journal article
Hereditary spastic paraplegia: gain-of-function mechanisms revealed by new transgenic mouse
Human molecular genetics, v 28(7), pp 1136-1152
01 Apr 2019
PMID: 30520996
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Mutations of the SPAST gene, which encodes the microtubule-severing protein spastin, are the most common cause of hereditary spastic paraplegia (HSP). Haploinsufficiency is the prevalent opinion as to the mechanism of the disease, but gain-of-function toxicity of the mutant proteins is another possibility. Here, we report a new transgenic mouse (termed SPASTC448Y mouse) that is not haploinsufficient but expresses human spastin bearing the HSP pathogenic C448Y mutation. Expression of the mutant spastin was documented from fetus to adult, but gait defects reminiscent of HSP (not observed in spastin knockout mice) were adult onset, as is typical of human patients. Results of histological and tracer studies on the mouse are consistent with progressive dying back of corticospinal axons, which is characteristic of the disease. The C448Y-mutated spastin alters microtubule stability in a manner that is opposite to the expectations of haploinsufficiency. Neurons cultured from the mouse display deficits in organelle transport typical of axonal degenerative diseases, and these deficits were worsened by depletion of endogenous mouse spastin. These results on the SPASTC448Y mouse are consistent with a gain-of-function mechanism underlying HSP, with spastin haploinsufficiency exacerbating the toxicity of the mutant spastin proteins. These findings reveal the need for a different therapeutic approach than indicated by haploinsufficiency alone.
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Details
- Title
- Hereditary spastic paraplegia: gain-of-function mechanisms revealed by new transgenic mouse
- Creators
- Liang Qiang - Department of Neurobiology and Anatomy.Emanuela Piermarini - Department of Neurobiology and Anatomy.Hemalatha Muralidharan - Department of Neurobiology and Anatomy.Wenqian Yu - Department of Neurobiology and Anatomy.Lanfranco Leo - Department of Neurobiology and Anatomy.Laura E Hennessy - Drexel UniversitySilvia Fernandes - Department of Neurobiology and Anatomy.Theresa Connors - Department of Neurobiology and Anatomy.Philip L Yates - Department of Neurobiology and Anatomy.Michelle Swift - Department of Neurobiology and Anatomy.Lyandysha V Zholudeva - Department of Neurobiology and Anatomy.Michael A Lane - Department of Neurobiology and Anatomy.Gerardo Morfini - University of Illinois at ChicagoGuillermo M Alexander - Drexel UniversityTerry D Heiman-Patterson - Drexel UniversityPeter W Baas - Department of Neurobiology and Anatomy.
- Publication Details
- Human molecular genetics, v 28(7), pp 1136-1152
- Publisher
- Oxford University Press
- Grant note
- R01 NS081112 / NINDS NIH HHS R01 NS028785 / NINDS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Neurobiology and Anatomy; [Retired Faculty]; Neurology
- Web of Science ID
- WOS:000463244700007
- Scopus ID
- 2-s2.0-85063303905
- Other Identifier
- 991019169627904721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Genetics & Heredity