, 2005) Two of the VCP mutations harbored by the patient fibrobl

, 2005). Two of the VCP mutations harbored by the patient fibroblasts are located at the N domain of the protein (R155H and R155C), whereas the third one is located in the link between the N and the D1 domain (R191Q). It was previously shown that none of IBMPFD mutations in VCP disrupt gross hexamer formation ( Halawani et al., 2009). The mitochondrial dysfunction observed in this study may help to explain the myopathic phenotype of VCP patients. Dementia is unusual in mitochondrial disorders, but mitochondrial dysfunction has also been suggested to be important in a number of central degenerative disorders such as SOD1-associated ALS (for review, see Dupuis

et al., 2003). In summary, we have characterized the mitochondrial pathology in fibroblasts from IBMFPD patients carrying VCP buy CT99021 mutations and identified a possible mechanism of neurotoxicity. Our data suggest that VCP deficiency leads to severe mitochondrial uncoupling, resulting in decreased ATP production and subsequent depletion of cellular ATP. This lack of ATP in turn renders VCP-deficient cells significantly more vulnerable to cytotoxicity in response to any further inhibition of mitochondrial respiration, and we propose that it is this Selleckchem Veliparib vulnerability to ischemic conditions that may ultimately cause the neuronal death observed in the IBMFPD patients. Detailed Experimental

Procedures can be found in the Supplemental Experimental Procedures.

All samples were collected with the written consent of participants and formal ethical approval from the National Hospital for Neurology and Neurosurgery–Institute of Neurology Joint Research Ethics Committee (London, UK). We are grateful to all patients and donors who helped make this work possible. F.B. is supported by a fellowship from the Spanish Ministerio de Educacion through the FECYT. This work was supported by a career development award from the MRC (G0700183), ALS Association Initiated award (ID 2109), Motor Neuron Disease Association, partially by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson’s Disease Consortium (UKPDC), and supported by the National Institute for Health Research University College London Hospitals Biomedical Electron transport chain Research Centre. A.C., A.C., C.J.M., J.M., and A.C are funded by European Community’s Health Seventh Framework Programme (FP7/2007–2013) (grant agreements 259867 and 278611). R.W.O. is funded by the Motor Neuron Disease Association (Grant 6040). Thanks to Dr. M. Cano who kindly provided us the mouse littermates, Dr. H. Imamura who provided us with the FRET-based ATP sensor, Dr. K. Wanish who provided us the Hek293T cell line used for the generation of lentiviral particles, and Dr. K.M. Holmstrom for her help in the experimental procedures and her advice in the writing of the manuscript. F.B.

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