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Behavioral and quantitative mitochondrial proteome analyses of the effects of simvastatin: implications for models of neural degeneration

  • Basic Neurosciences, Genetics and Immunology - Original Article
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Journal of Neural Transmission Aims and scope Submit manuscript

An Erratum to this article was published on 21 August 2009

Abstract

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, simvastatin, is used for lowering elevated low-density lipoprotein cholesterol concentrations. This translates into reduced cardiovascular disease-related morbidity and mortality, while the drugs’ anti-oxidant and anti-inflammatory properties have earmarked it as a potential treatment strategy against various neurological conditions. Statins have been shown to protect neurons from degeneration in a number of animal models. Although no mechanism completely explains the multiple benefits exerted by statins, emerging evidence suggests that in some degenerative and brain injury models, mitochondrial impairment may play a contributive rate. However, there evidence lacks to support a directly influencing role for statins on mitochondria-related proteins and motor behavior. Mitochondrial dysfunction may increase oxygen free radical production, which in turn leaves cells susceptible to energy failure, apoptosis and related events the occurance of which could prove fatal. The potential link between simvastatin treatment and mitochondrial function would be supported if key mitochondrial proteins were altered by simvastatin exposure. Using mass spectroscopy (MS), we identified 24 mitochondrial proteins that differed significantly (P < 0.05) in relative abundancy as a result of simvastatin treatment. The identified proteins represented many facets of mitochondrial integrity, with the majority forming part of the electron transport chain machinery, which is necessary for energy production. In a follow-up study, we then addressed whether simvastatin is capable of altering sensorimotor function in a mitochondrial toxin-induced animal model. Rats were pre-treated with simvastatin for 14 days, followed by a single unihemispheric (substantia nigra; SN) injection of rotenone, a mitochondrial complex I (Co-I) inhibitor. Results showed that simvastatin improved motor performance in rotenone-infused rats. The data are consistent with the possibility that alteration of mitochondrial function may contribute to the beneficial effects associated with statin use.

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Abbreviations

SNCA:

Alpha(α)-synuclein

BSA:

Bovine serum albumin

Co-I:

Complex I

DRP-2:

Dihydropyrimidinase related protein 2

DA-ergic:

Dopaminergic

IEF:

Isoelectric focusing

NF:

Neurofilament

NSE:

Neuronal-specific enolase

p + r:

Placebo + rotenone

p + v:

Placebo + vehicle

PD:

Parkinson’s disease

PTPRF:

Protein tyrosine, receptor type F, polypeptide interacting protein

ROS:

Reactive oxygen species

SD:

Sprague–Dawley

SN:

Substantia nigra

TBS:

Tris–buffered saline

2-DE:

Two-dimensional gel electrophoresis

UPS:

Ubiquitin–proteasome system

s + v:

Statin + vehicle

s + r:

Statin + rotenone

MS:

Mass spectrometry

METC:

Mitochondrial electron transport chain

ESI-QUAD-TOF:

Quadripole time-of-flight

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Acknowledgments

I·P. is supported by a John G. Nicholls Post-Doctoral Research Fellowship, awarded by the International Brain Research Organisation. The financial assistance of the National Research Foundation (NRF) of South Africa toward this research is hereby also acknowledged. The help provided by Prof. Martin Kidd from the Department of Statistics, University of Stellenbosch, for statistically analyzing the data is appreciated. We also thank Dr. Leanne Loijens from Noldus in the Netherlands for helping to set up the behavior tracking software. We thank Lorren Fairbairn for providing technical assistance. We also thank the Davis Phinney Foundation.

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Authors and Affiliations

  1. MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK

    Ilse S. Pienaar

  2. Department of Medical Physiology, University of Stellenbosch, Tygerberg, South Africa

    Ilse S. Pienaar & Suzél Hattingh

  3. Departments of Psychology and Neurobiology, University of Texas at Austin, Austin, USA

    Timothy Schallert

  4. Department of Medicine, University of Kwazulu-Natal, Congella, South Africa

    William M. U. Daniels

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  1. Ilse S. Pienaar
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  2. Timothy Schallert
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  3. Suzél Hattingh
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  4. William M. U. Daniels
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Correspondence to Ilse S. Pienaar.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00702-009-0280-3

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Pienaar, I.S., Schallert, T., Hattingh, S. et al. Behavioral and quantitative mitochondrial proteome analyses of the effects of simvastatin: implications for models of neural degeneration. J Neural Transm 116, 791–806 (2009). https://doi.org/10.1007/s00702-009-0247-4

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