PEX13 deficiency in mouse brain as a model of Zellweger syndrome : Abnormal cerebellum formation, reactive gliosis and oxidative stress

Muller, C. Catharina, Nguyen, Tam H., Ahlemeyer, Barbara, Meshram, Mallika, Santrampurwala, Nishreen, Cao, Siyu, Sharp, Peter, Fietz, Pamela B., Baumgart-Vogt, Eveline and Crane, Denis I. (2011) PEX13 deficiency in mouse brain as a model of Zellweger syndrome : Abnormal cerebellum formation, reactive gliosis and oxidative stress. Disease Models and Mechanisms, 4 1: 104-119. doi:10.1242/dmm.004622


Author Muller, C. Catharina
Nguyen, Tam H.
Ahlemeyer, Barbara
Meshram, Mallika
Santrampurwala, Nishreen
Cao, Siyu
Sharp, Peter
Fietz, Pamela B.
Baumgart-Vogt, Eveline
Crane, Denis I.
Title PEX13 deficiency in mouse brain as a model of Zellweger syndrome : Abnormal cerebellum formation, reactive gliosis and oxidative stress
Journal name Disease Models and Mechanisms   Check publisher's open access policy
ISSN 1754-8403
1754-8411
Publication date 2011-01-01
Sub-type Article (original research)
DOI 10.1242/dmm.004622
Open Access Status DOI
Volume 4
Issue 1
Start page 104
End page 119
Total pages 6
Place of publication Cambridge, United Kingdom
Publisher The Company of Biologists
Language eng
Formatted abstract
Delayed cerebellar development is a hallmark of Zellweger syndrome (ZS), a severe neonatal neurodegenerative disorder. ZS is caused by mutations in PEX genes, such as PEX13, which encodes a protein required for import of proteins into the peroxisome. The molecular basis of ZS pathogenesis is not known. We have created a conditional mouse mutant with brain-restricted deficiency of PEX13 that exhibits cerebellar morphological defects. PEX13 brain mutants survive into the postnatal period, with the majority dying by 35 days, and with survival inversely related to litter size and weaning body weight. The impact on peroxisomal metabolism in the mutant brain is mixed: plasmalogen content is reduced, but very-long-chain fatty acids are normal. PEX13 brain mutants exhibit defects in reflex and motor development that correlate with impaired cerebellar fissure and cortical layer formation, granule cell migration and Purkinje cell layer development. Astrogliosis and microgliosis are prominent features of the mutant cerebellum. At the molecular level, cultured cerebellar neurons from E19 PEX13-null mice exhibit elevated levels of reactive oxygen species and mitochondrial superoxide dismutase-2 (MnSOD), and show enhanced apoptosis together with mitochondrial dysfunction. PEX13 brain mutants show increased levels of MnSOD in cerebellum. Our findings suggest that PEX13 deficiency leads to mitochondria-mediated oxidative stress, neuronal cell death and impairment of cerebellar development. Thus, PEX13-deficient mice provide a valuable animal model for investigating the molecular basis and treatment of ZS cerebellar pathology.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ
Additional Notes First posted online October 19, 2010

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
Queensland Brain Institute Publications
ERA 2012 Admin Only
 
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Citation counts: TR Web of Science Citation Count  Cited 22 times in Thomson Reuters Web of Science Article | Citations
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Created: Sat, 15 Oct 2011, 03:50:59 EST by Mr Tam Nguyen on behalf of Queensland Brain Institute