Impaired Mitochondrial Fatty Acid Synthesis Leads to Neurodegeneration in Mice

被引:28
|
作者
Nair, Remya R. [1 ]
Koivisto, Henna [4 ]
Jokivarsi, Kimmo [4 ]
Miinalainen, Ilkka J. [2 ]
Autio, Kaija J. [1 ]
Manninen, Aki [1 ,3 ]
Poutiainen, Pekka [5 ]
Tanila, Heikki [4 ]
Hiltunen, J. Kalervo [1 ]
Kastaniotis, Alexander J. [1 ]
机构
[1] Univ Oulu, Fac Biochem & Mol Med, POB 5400, FI-90014 Oulu, Finland
[2] Univ Oulu, Electron Microscopy Core Facil, FI-90014 Oulu, Finland
[3] Univ Oulu, Virus Core Facil, Bioctr Oulu, FI-90014 Oulu, Finland
[4] Univ Eastern Finland, AI Virtanen Inst, FI-70211 Kuopio, Finland
[5] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, FI-70029 Kuopio, Finland
来源
JOURNAL OF NEUROSCIENCE | 2018年 / 38卷 / 45期
基金
芬兰科学院;
关键词
ataxia; Mecr; mitochondria; mitochondrial fatty acid synthesis; neurodegeneration; Purkinje cells; CEREBELLAR PURKINJE-CELLS; COMPLEX-I DEFICIENCY; PROTEIN; DYSFUNCTION; MOUSE; BIOGENESIS; MUTATIONS; ATAXIA; SUPEROXIDE; MECHANISMS;
D O I
10.1523/JNEUROSCI.3514-17.2018
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 similar to 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.
引用
收藏
页码:9781 / 9800
页数:20
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