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Increased Expression of MicroRNA-29a in ALS Mice: Functional Analysis of Its Inhibition

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Abstract

Endoplasmic reticulum (ER) stress has been implicated in a number of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). MicroRNAs are small ribonucleic acids which can modulate protein expression by binding to the 3′UTR of target mRNAs. We recently identified increased miR-29a expression in response to ER stress in neurons, with members of the miR-29 family implicated in cancer and neurodegeneration. We found high expression of miR-29a in the mouse brain and spinal cord by quantitative PCR analysis and increased expression of miR-29a in the spinal cord of SOD1G93A transgenic mice, a mouse model of familial ALS. In situ hybridisation experiments revealed increased miR-29a expression in the lumbar spinal cord of SOD1G93A transgenic mice from postnatal day 70 onward when compared to wild-type mice. miR-29a knockdown was achieved in the CNS in vivo after a single intracerebroventricular injection of a miR-29a-specific antagomir. While analysis of disease progression and motor function could not identify a significant alteration in ALS disease manifestations, a trend towards increased lifespan was observed in male SOD1G93A mice. These findings demonstrate that miR-29a may act as a marker for disease progression in SOD1G93A mice, and provide first proof-of-concept for a therapeutic modulation of miR-29a function in ALS.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

aCSF:

Artificial cerebrospinal fluid

CNS:

Central nervous system

DIG:

Digoxigenin

ER:

Endoplasmic reticulum

fALS:

Familial amyotrophic lateral sclerosis

ICV:

Intracerebroventricular

LNA:

Locked nucleic acid

PND:

Postnatal day

RT-qPCR:

Quantitative real-time polymerase chain reaction

SOD1:

Superoxide dismutase 1

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Acknowledgments

We would like to thank Dr. Ross McKiernan and Dr. Gang Chen for their expertise and teaching of surgical procedures, Ms. Simone Poeschel for technical assistance and Prof. J. Waddington for use of mouse phenotyping equipment. This work was funded by grants from Science Foundation Ireland (08/IN.1/1949; 12/COEN/18—Joint Programming in Neurodegenerative Disorders, COEN-Phase II, ‘Neuro-miR’) to J.H.M.P., and by a Health Research Board Ph.D. Scholarship to K.N. (PHD/2007/11).

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The authors declare that they have no competing interests.

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  1. Centre for the Study of Neurological Disorders, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 2, Ireland

    Katie Nolan, Mollie R. Mitchem, Eva M. Jimenez-Mateos, David C. Henshall, Caoimhín G. Concannon & Jochen H. M. Prehn

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  1. Katie Nolan
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  2. Mollie R. Mitchem
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Correspondence to Jochen H. M. Prehn.

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Nolan, K., Mitchem, M.R., Jimenez-Mateos, E.M. et al. Increased Expression of MicroRNA-29a in ALS Mice: Functional Analysis of Its Inhibition. J Mol Neurosci 53, 231–241 (2014). https://doi.org/10.1007/s12031-014-0290-y

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