Defined Neuronal Populations Drive Fatal Phenotype in a Mouse Model of Leigh Syndrome

Overview

Journal Elife

Specialty Biology

Date 2019 Aug 13

PMID 31403401

Citations 25

Authors

Irene Bolea

Alejandro Gella

Elisenda Sanz

Patricia Prada-Dacasa

Fabien Menardy

Angela M Bard

Pablo Machuca-Marquez

Abel Eraso-Pichot

Guillem Modol-Caballero

Xavier Navarro

Franck Kalume

Albert Quintana

Affiliations

Soon will be listed here.

Abstract

Mitochondrial deficits in energy production cause untreatable and fatal pathologies known as mitochondrial disease (MD). Central nervous system affectation is critical in Leigh Syndrome (LS), a common MD presentation, leading to motor and respiratory deficits, seizures and premature death. However, only specific neuronal populations are affected. Furthermore, their molecular identity and their contribution to the disease remains unknown. Here, using a mouse model of LS lacking the mitochondrial complex I subunit , we dissect the critical role of genetically-defined neuronal populations in LS progression. inactivation in Vglut2-expressing glutamatergic neurons leads to decreased neuronal firing, brainstem inflammation, motor and respiratory deficits, and early death. In contrast, deletion in GABAergic neurons causes basal ganglia inflammation without motor or respiratory involvement, but accompanied by hypothermia and severe epileptic seizures preceding death. These results provide novel insight in the cell type-specific contribution to the pathology, dissecting the underlying cellular mechanisms of MD.

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References

Finsterer J . Toxicity of Antiepileptic Drugs to Mitochondria. Handb Exp Pharmacol. 2016; 240:473-488. DOI: 10.1007/164_2016_2. View

Kruse S, Watt W, Marcinek D, Kapur R, Schenkman K, Palmiter R . Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy. Cell Metab. 2008; 7(4):312-20. PMC: 2593686. DOI: 10.1016/j.cmet.2008.02.004. View

McKelvie P, Infeld B, Marotta R, Chin J, Thorburn D, Collins S . Late-adult onset Leigh syndrome. J Clin Neurosci. 2012; 19(2):195-202. DOI: 10.1016/j.jocn.2011.09.009. View

Ferrari M, Jain I, Goldberger O, Rezoagli E, Thoonen R, Cheng K . Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome. Proc Natl Acad Sci U S A. 2017; 114(21):E4241-E4250. PMC: 5448167. DOI: 10.1073/pnas.1621511114. View

Taniguchi H, He M, Wu P, Kim S, Paik R, Sugino K . A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron. 2011; 71(6):995-1013. PMC: 3779648. DOI: 10.1016/j.neuron.2011.07.026. View

Rossi J, Balthasar N, Olson D, Scott M, Berglund E, Lee C . Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab. 2011; 13(2):195-204. PMC: 3033043. DOI: 10.1016/j.cmet.2011.01.010. View

Juge N, Gray J, Omote H, Miyaji T, Inoue T, Hara C . Metabolic control of vesicular glutamate transport and release. Neuron. 2010; 68(1):99-112. PMC: 2978156. DOI: 10.1016/j.neuron.2010.09.002. View

Gubellini P, Picconi B, Di Filippo M, Calabresi P . Downstream mechanisms triggered by mitochondrial dysfunction in the basal ganglia: from experimental models to neurodegenerative diseases. Biochim Biophys Acta. 2009; 1802(1):151-61. DOI: 10.1016/j.bbadis.2009.08.001. View

Sanz E, Yang L, Su T, Morris D, McKnight G, Amieux P . Cell-type-specific isolation of ribosome-associated mRNA from complex tissues. Proc Natl Acad Sci U S A. 2009; 106(33):13939-44. PMC: 2728999. DOI: 10.1073/pnas.0907143106. View

10.

Bochorishvili G, Stornetta R, Coates M, Guyenet P . Pre-Bötzinger complex receives glutamatergic innervation from galaninergic and other retrotrapezoid nucleus neurons. J Comp Neurol. 2011; 520(5):1047-61. PMC: 3925347. DOI: 10.1002/cne.22769. View

11.

Zimin P, Woods C, Quintana A, Ramirez J, Morgan P, Sedensky M . Glutamatergic Neurotransmission Links Sensitivity to Volatile Anesthetics with Mitochondrial Function. Curr Biol. 2016; 26(16):2194-201. PMC: 5007115. DOI: 10.1016/j.cub.2016.06.020. View

12.

Kim H, Choi W, Sorscher N, Park H, Tronche F, Palmiter R . Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo. Neurobiol Aging. 2015; 36(9):2617-27. PMC: 4523431. DOI: 10.1016/j.neurobiolaging.2015.05.008. View

13.

Queiroz C, Gorter J, Lopes da Silva F, Wadman W . Dynamics of evoked local field potentials in the hippocampus of epileptic rats with spontaneous seizures. J Neurophysiol. 2008; 101(3):1588-97. DOI: 10.1152/jn.90770.2008. View

14.

Oakley J, Kalume F, Yu F, Scheuer T, Catterall W . Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy. Proc Natl Acad Sci U S A. 2009; 106(10):3994-9. PMC: 2656193. DOI: 10.1073/pnas.0813330106. View

15.

Kalume F, Westenbroek R, Cheah C, Yu F, Oakley J, Scheuer T . Sudden unexpected death in a mouse model of Dravet syndrome. J Clin Invest. 2013; 123(4):1798-808. PMC: 3613924. DOI: 10.1172/JCI66220. View

16.

Bayraktar E, Baudrier L, Ozerdem C, Lewis C, Chan S, Kunchok T . MITO-Tag Mice enable rapid isolation and multimodal profiling of mitochondria from specific cell types in vivo. Proc Natl Acad Sci U S A. 2018; 116(1):303-312. PMC: 6320505. DOI: 10.1073/pnas.1816656115. View

17.

Barends M, Verschuren L, Morava E, Nesbitt V, Turnbull D, McFarland R . Causes of Death in Adults with Mitochondrial Disease. JIMD Rep. 2015; 26:103-13. PMC: 4864865. DOI: 10.1007/8904_2015_449. View

18.

Johnson S, Yanos M, Kayser E, Quintana A, Sangesland M, Castanza A . mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science. 2013; 342(6165):1524-8. PMC: 4055856. DOI: 10.1126/science.1244360. View

19.

Ramadasan-Nair R, Hui J, Itsara L, Morgan P, Sedensky M . Mitochondrial Function in Astrocytes Is Essential for Normal Emergence from Anesthesia in Mice. Anesthesiology. 2019; 130(3):423-434. PMC: 6375739. DOI: 10.1097/ALN.0000000000002528. View

20.

Quintana A, Zanella S, Koch H, Kruse S, Lee D, Ramirez J . Fatal breathing dysfunction in a mouse model of Leigh syndrome. J Clin Invest. 2012; 122(7):2359-68. PMC: 3387817. DOI: 10.1172/JCI62923. View