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Impaired mitochondrial fatty acid synthesis leads to neurodegeneration in mice

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published version
Date
2018
Author(s)
Nair, Remya R
Koivisto, Henna
Jokivarsi, Kimmo
Miinalainen, Ilkka J
Autio, Kaija J
Manninen, Aki
Poutiainen, Pekka
Tanila, Heikki
Hiltunen, J Kalervo
Kastaniotis, Alexander J
Unique identifier
10.1523/JNEUROSCI.3514-17.2018
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Citation
Nair, Remya R. Koivisto, Henna. Jokivarsi, Kimmo. Miinalainen, Ilkka J. Autio, Kaija J. Manninen, Aki. Poutiainen, Pekka. Tanila, Heikki. Hiltunen, J Kalervo. Kastaniotis, Alexander J. (2018). Impaired mitochondrial fatty acid synthesis leads to neurodegeneration in mice.  JOURNAL OF NEUROSCIENCE, 38 (45) , 9781-9800. 10.1523/JNEUROSCI.3514-17.2018.
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Abstract

There has been a growing interest toward mitochondrial fatty acid synthesis (mtFAS) since the recent discovery of a neurodegenerative human disorder termed MEPAN (mitochondrial enoyl reductase protein associated neurodegeneration), which is caused by mutations in the mitochondrial enoyl-CoA/ACP (acyl carrier protein) reductase (MECR) carrying out the last step of mtFAS. We show here that MECR protein is highly expressed in mouse Purkinje cells (PCs). To elucidate mtFAS function in neural tissue, here, we generated a mouse line with a PC-specific knock-out (KO) of Mecr, leading to inactivation of mtFAS confined to this cell type. Both sexes were studied. The mitochondria in KO PCs displayed abnormal morphology, loss of protein lipoylation, and reduced respiratory chain enzymatic activities by the time these mice were 6 months of age, followed by nearly complete loss of PCs by 9 months of age. These animals exhibited balancing difficulties ∼7 months of age and ataxic symptoms were evident from 8–9 months of age on. Our data show that impairment of mtFAS results in functional and ultrastructural changes in mitochondria followed by death of PCs, mimicking aspects of the clinical phenotype. This KO mouse represents a new model for impaired mitochondrial lipid metabolism and cerebellar ataxia with a distinct and well trackable cellular phenotype. This mouse model will allow the future investigation of the feasibility of metabolite supplementation approaches toward the prevention of neurodegeneration due to dysfunctional mtFAS.

Subjects
ataxia   Mecr   mitochondria   mitochondrial fatty acid synthesis   neurodegeneration   Purkinje cells   
URI
https://erepo.uef.fi/handle/123456789/7178
Link to the original item
http://dx.doi.org/10.1523/JNEUROSCI.3514-17.2018
Publisher
Society for Neuroscience
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  • Terveystieteiden tiedekunta [1324]
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