Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for coordinated movement in mice

Molecular Neurodegeneration

Gopal Thinakaran¹  Angèle T Parent¹  Satyabrata Kar⁵  Lois A Zitzow³  Vytautas P Bindokas⁴  Kulandaivelu S Vetrivel¹  Celia G Fernandez²  Jelita Roseman¹  Ping Gong¹ 

[1] Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL, 60637, USA;Committee on Neurobiology, The University of Chicago, Chicago, IL, 60637, USA;Department of Surgery, The University of Chicago, Chicago, IL, 60637, USA;Department of Neurobiology, Pharmacology, and Physiology, The University of Chicago, Chicago, IL, 60637, USA;Departments of Medicine and Psychiatry, Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, T6G 2R7, Canada

关键词: unfolded protein response;    hypomyelination;    ataxia;    Alzheimer's disease;    gamma-secretase;    p24;   

Others  :  863979
DOI  :  10.1186/1750-1326-6-87

 received in 2011-08-09, accepted in 2011-12-28,  发布年份 2011

【 摘 要 】

Background

p23 belongs to the highly conserved p24 family of type I transmembrane proteins, which participate in the bidirectional protein transport between the endoplasmic reticulum and Golgi apparatus. Mammalian p23 has been shown to interact with γ-secretase complex, and modulate secretory trafficking as well as intramembranous processing of amyloid precursor protein in cultured cells. Negative modulation of β-amyloid production by p23 in cultured cell lines suggested that elevation of p23 expression in neurons might mitigate cerebral amyloid burden.

Results

We generated several lines of transgenic mice expressing human p23 in neurons under the control of Thy-1.2 promoter. We found that even a 50% increase in p23 levels in the central nervous system of mice causes post-natal growth retardation, severe neurological problems characterized by tremors, seizure, ataxia, and uncoordinated movements, and premature death. The severity of the phenotype closely correlated with the level of p23 overexpression in multiple transgenic lines. While the number and general morphology of neurons in Hup23 mice appeared to be normal throughout the brain, abnormal non-Golgi p23 localization was observed in a subset of neurons with high transgene expression in brainstem. Moreover, detailed immunofluorescence analysis revealed marked proliferation of astrocytes, activation of microglia, and thinning of myelinated bundles in brainstem of Hup23 mice.

Conclusions

These results demonstrate that proper level of p23 expression is critical for neuronal function, and perturbing p23 function by overexpression initiates a cascade of cellular reactions in brainstem that leads to severe motor deficits and other neurological problems, which culminate in premature death. The neurological phenotype observed in Hup23 mice highlights significant adverse effects associated with manipulating neuronal expression of p23, a previously described negative modulator of γ-secretase activity and β-amyloid production. Moreover, our report has broader relevance to molecular mechanisms in several neurodegenerative diseases as it highlights the inherent vulnerability of the early secretory pathway mechanisms that ensure proteostasis in neurons.

【 授权许可】

   
2011 Gong et al; licensee BioMed Central Ltd.

【 图 表 】

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