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Right arrow Stroke in young adults
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Neurology 2001;57:1235-1238
© 2001 American Academy of Neurology
Articles

Mitochondrial dysfunction associated with a mutation in the Notch3 gene in a CADASIL family

P. de la Peña, MSc, B. Bornstein, MD, P. del Hoyo, MSc, M. A. Fernández–Moreno, PhD, M. A. Martín, PharB, Y. Campos, MSc, C. Gómez–Escalonilla, MD, J. A. Molina, MD, A. Cabello, MD, J. Arenas, PhD and R. Garesse, PhD

From the Departamento de Bioquímica (Drs. Bornstein, Fernández–Moreno, and Garesse, and P. de la Peña), Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Facultad de Medicina, Universidad Autónoma de Madrid; Centro de Investigación (Dr. Arenas, P. del Hoyo, A. Martín, and Y. Campos), Hospital Universitario "12 de Octubre"; Hospital Severo Ochoa (Dr. Bornstein), Leganés; Servicio de Neurología (Drs. Gómez-Escalonilla, and Molina), Hospital Universitario "12 de Octubre"; and Sección de Neuropatología (Dr. Cabello), Hospital Universitario "12 de Octubre", Madrid, Spain.

Address correspondence and reprint requests to Dr. Rafael Garesse, Departamento de Bioquímica, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Facultad de Medicina, Universidad Autónoma de Madrid, c/Arzobispo Morcillo 4, 28029 Madrid, Spain; e-mail: rafael.garesse{at}uam.es

Background: Cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by recurrent subcortical ischemic strokes and dementia caused by mutations in the Notch3 gene. In Drosophila melanogaster, Notch signaling has a pleiotropic effect, affecting most tissues of the organism during development. Objective: To characterize a potential mitochondrial dysfunction associated with mutations in the Notch3 gene. Methods: Biochemical, histochemical, molecular, and genetic analyses were performed on muscle biopsy specimens and fibroblasts obtained from patients of a Spanish family with CADASIL. Additional biochemical and molecular analyses of the N55e11 mutant of D. melanogaster were performed. Results: In muscle biopsy specimens, a significant decrease was found in the activity of complex I (NADH [reduced form of nicotinamide adenine dinucleotide] dehydrogenase), and in one patient, histochemical analysis showed the presence of ragged-red fibers with abnormal cytochrome c oxidase staining. Reduced fibroblast activity of complex V (ATP synthase) was found. Supporting data on patients with CADASIL, it was found that the mutation N55e11 in Drosophila decreases the activity of mitochondrial respiratory complexes I and V. Conclusions: Mitochondrial respiratory chain activity responds, directly or indirectly, to the Notch signaling pathway. Mitochondrial dysfunction in patients with CADASIL may be an epiphenomenon, but results of this study suggest that the pathophysiology of the disease could include a defect in oxidative phosphorylation.




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