期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 15, 页码 10769-10784出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.515940
关键词
Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease); Mitochondrial Metabolism; Mouse Genetics; Mutagenesis Site-specific; Neurological Diseases
资金
- KNDD2 Grant [FKZ 01 GI 1005D]
- Federal Ministry for Education and Research (BMBF) [01GS08133]
- grant Verhalten [01GS0850]
- Helmholtz Alliance Mental Health in an Aging Society (HELMA) [HA215]
- Cluster of Excellence Frankfurt Macromolecular Complexes at the Goethe University Frankfurt DFG [EXC 115]
- German Federal Ministry of Education and Research (BMBF)
- German Center for Diabetes Research (DZD e.V.)
- NGFN plus [01GS0850]
- BMBF [01KX1012]
- EU [EUMODIC LSHG-2006-037188]
- National Genome Research Network [NGFN 01GR]
- German Federal Ministry of Education and Research (German Center for Vertigo and Balance Disorders) [01 EO 0901]
Background: Mutations in TDP-43 are frequently found in ALS patients. Results: A315T TDP-43 protein is elevated from this transgenic knock-in allele due to disturbed feedback regulation. Conclusion: Elevation of A315T TDP-43 was insufficient to cause ALS in this mutant. Significance: This TDP-43 allele could be valuable in determining genetic or environmental factors that cause full-blown FTLD or ALS. The majority of amyotrophic lateral sclerosis (ALS) cases as well as many patients suffering from frontotemporal lobar dementia (FTLD) with ubiquitinated inclusion bodies show TDP-43 pathology, the protein encoded by the TAR DNA-binding protein (Tardbp) gene. We used recombinase-mediated cassette exchange to introduce an ALS patient cDNA into the mouse Tdp-43 locus. Expression levels of human A315T TDP-43 protein were 300% elevated in heterozygotes, whereas the endogenous mouse Tdp-43 was decreased to 20% of wild type levels as a result of disturbed feedback regulation. Heterozygous TDP-43(A315TKi) mutants lost 10% of their body weight and developed insoluble TDP-43 protein starting as early as 3 months after birth, a pathology that was exacerbated with age. We analyzed the splicing patterns of known Tdp-43 target genes as well as genome-wide gene expression levels in different tissues that indicated mitochondrial dysfunction. In heterozygous mutant animals, we observed a relative decrease in expression of Parkin (Park2) and the fatty acid transporter CD36 along with an increase in fatty acids, HDL cholesterol, and glucose in the blood. As seen in transmission electron microscopy, neuronal cells in motor cortices of TDP-43(A315TKi) animals had abnormal neuronal mitochondrial cristae formation. Motor neurons were reduced to 90%, but only slight motoric impairment was detected. The observed phenotype was interpreted as a predisease model, which might be valuable for the identification of further environmental or genetic triggers of neurodegeneration.
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