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Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurobiology.
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2004 In: Biochemical and Biophysical Research Communications, ISSN 0006-291X, Vol. 322, no 1, 281-286 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2004. Vol. 322, no 1, 281-286 p.
URN: urn:nbn:se:uu:diva-95176OAI: oai:DiVA.org:uu-95176DiVA: diva2:169292
Available from: 2006-11-24 Created: 2006-11-24Bibliographically approved
In thesis
1. Amyotrophic Lateral Sclerosis – A Study in Transgenic Mice
Open this publication in new window or tab >>Amyotrophic Lateral Sclerosis – A Study in Transgenic Mice
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an incidence of 1.5-2.7/100000 people/year. Today there is no cure for the disease and only symptomatic treatments are available. ALS progresses rapidly and only 50% of the patients are alive three years after the symptom debut. In ALS, the upper and lower motor neurons undergo degeneration in a process resembling apoptosis. This leads to muscle atrophy and paralysis. The causes of neuronal death are however unknown. In this thesis we have studied transgenic mice carrying human mutant superoxide dismutase, as a model for familial ALS. These mice develop ALS-like symptoms after four months of age with degeneration of the motor neurons. Our results show an involvement of endoplasmic reticulum stress, caspase-12, -9, -3 and procaspase-7 in the ALS mice spinal cord. Overexpression of the antiapoptotic protein XIAP in spinal cord neurons inhibited the activation of caspase-12 and reduced caspase-3 and calpain activity. Calpastatin, the regulator of calpain activity, was kept intact in the ALS-XIAP mice. These mice showed a 12% increase in the mean survival suggesting a beneficial effect of XIAP in ALS. The reason for the ultimate cell death of motor neurons in the ALS-XIAP mice may be due to the activation of additional cell death pathways. Thus, we observed that lysosomal proteases particularly, cathepsinB, -D, and -L were activated in the ALS mice spinal cord together with a less marked upregulation of the inhibitors, cystatinB and -C. We also found activation of astrocytes and microglial cells in the spinal cord of ALS mice indicating their involvement in the disease. The results show that both caspase-dependent and -independent pathways are activated during neuronal degeneration in the ALS spinal cord. The results obtained may help to identify novel drug targets for future treatments of ALS.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 57 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 205
Neurosciences, ALS, Caspase, Caspase-12, Cathepsin, Cystatin, ER stress, Motor neuron, Neurodegeneration, Sod1, XIAP, Neurovetenskap
urn:nbn:se:uu:diva-7342 (URN)91-554-6730-X (ISBN)
Public defence
2006-12-15, B41, BMC, Husargatan 3, 75123, Uppsala, 13:15
Available from: 2006-11-24 Created: 2006-11-24Bibliographically approved

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