title: Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in mice.
abstract: Cells rely on efficient protein quality control systems (PQCs) to maintain proper activity of mitochondrial proteins. As part of this system, the mitochondrial chaperone Hsp60 assists folding of matrix proteins and it is an essential protein in all organisms. Mutations in Hspd1, the gene encoding Hsp60, are associated with two human inherited diseases of the nervous system, a dominantly inherited form of spastic paraplegia (SPG13) and an autosomal recessively inherited white matter disorder termed MitCHAP60 disease. Although the connection between mitochondrial failure and neurodegeneration is well known in many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease, and hereditary spastic paraplegia, the molecular basis of the neurodegeneration associated with these diseases is still ill-defined. Here, we investigate mice heterozygous for a knockout allele of the Hspd1 gene encoding Hsp60. Our results demonstrate that Hspd1 haploinsufficiency is sufficient to cause a late onset and slowly progressive deficit in motor functions in mice. We furthermore emphasize the crucial role of the Hsp60 chaperone in mitochondrial function by showing that the motor phenotype is associated with morphological changes of mitochondria, deficient ATP synthesis, and in particular, a defect in the assembly of the respiratory chain complex III in neuronal tissues. In the current study, we propose that our heterozygous Hsp60 mouse model is a valuable model system for the investigation of the link between mitochondrial dysfunction and neurodegeneration.
authors: Research Unit for Molecular Medicine, Department of Clinical Medicine, Health Aarhus University Hospital and Aarhus University, Aarhus, Denmark. raffaella.magnoni@ki.au.dk
authors: Raffaella
authors: R
authors: Magnoni
authors: Johan
authors: J
authors: Palmfeldt
authors: Jane H
authors: JH
authors: Christensen
authors: Majken
authors: M
authors: Sand
authors: Francesca
authors: F
authors: Maltecca
authors: Thomas J
authors: TJ
authors: Corydon
authors: Mark
authors: M
authors: West
authors: Giorgio
authors: G
authors: Casari
authors: Peter
authors: P
authors: Bross
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018834:Chaperonin 60 / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics; D016472:Motor Neuron Disease / Q000235:genetics / Q000503:physiopathology*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018834:Chaperonin 60; D045222:Electron Transport Chain Complex Proteins; C557066:Hspd1 protein, mouse; D024101:Mitochondrial Proteins