Abnormal mitochondrial organization and function
This French study of SPG31 HSP has found abnormal mitochondrial network organisation and defective mitochondrial energy production in all patients studied. The results suggest the direct involvement of the mitochondrial dysfunction in SPG31 HSP.
Objective: To decipher the pathophysiological mechanisms involved in SPG31 determinism.
Background Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized at least by slowly progressive spasticity of the lower limbs. Mutations in REEP1 were recently associated with SPG31, a pure dominant HSP. We recently identified 12 different heterozygous mutations in REEP1 by screening 175 unrelated HSP index patients from kindreds with dominant inheritance (AD-HSP), associated with either a pure or a complex phenotype. The overall mutation rate in our clinically heterogeneous sample was 4.5% in French families with AD-HSP. The phenotype was restricted to pyramidal signs in the lower limbs in most patients but 9 had a complex phenotype.
Design/Methods: We performed analyses on primary cultures of fibroblasts in 5 patients from 2 unrelated SPG31 families. In family 1 (one patient), the mutation c.103delG, p.Val36SerfsX4 was identified in exon 3 of REEP1. In family 2 (4 patients), the mutation c.124T>C, p.Trp42Arg was identified in exon 3 of REEP1.
Results: We evidenced abnormal mitochondrial network organization in fibroblasts of all patients from two SPG31 families in addition to defective mitochondrial energy production in both fibroblasts and muscle. The localization of some mitochondrial proteins appeared dramatically impaired in all the fibroblasts studied.
Conclusions: The alteration of mitochondrial morphogenesis seems correlated to the type of mutation. Studies of potential partners of REEP1 highlight the crucial role of mitochondrial fusion-fission balance in the pathogenesis of SPG31 and suggest a direct involvement of mitochondrial dysfunction in this neurodegenerative condition.
Supported by: Association contre les maladies mitochondriales (AMMi), Association Strumpell-Lorrain (ASL).
SOURCE: Neurology April 24, 2012; 78(Meeting Abstracts 1): IN7-1.007 doi: 10.1212/WNL.78.1
Mitochondrial Morpho-Functional Dysfunction in SPG31 Patients
Cyril Goizet1, Giovanni Benard2, Christel Depienne3, Amir Boukhris4, Guilhem Sole5, Isabelle Coupry6, Julie Pilliod7, Marie-Laure Martin-Négrier8, Sylvie Forlani9, Alexandra Durr10, Alexis Brice11, Didier Lacombe12, Rodrigue Rossignol13 and Giovanni Stevanin14
1 Laboratoire Maladies Rares: Génétique et Métabolisme Université Bordeaux, CHU Bordeaux Bordeaux France 2 Laboratoire MRGM CNRS, Université Bordeaux Bordeaux France 3 ICM Paris France 4 ICM Paris France 5 CHU Bordeaux Pessac France 6 laboratoire Maladies Rares: Génétique et Métabolisme Université Bordeaux Bordeaux France 7 Laboratoire Maladies Rares: Génétique et Métabolisme Université Bordeaux Bordeaux France 8 CHU Bordeaux, Université Bordeaux Bordeaux France 9 ICM Paris France 10 Hopital de la Salpetriere Paris France 11 ICM Hopital de la Salpetriere Paris France 12 Université Bordeaux, CHU Bordeaux Bordeaux France 13 Université Bordeaux, INSERM Bordeaux France 14 ICM Paris France