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Human Molecular Genetics, 2001, Vol. 10, No. 19 2143-2155
© 2001 Oxford University Press

Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1

Nicolas Sergeant1, Bernard Sablonnière1, Suzanna Schraen-Maschke1, Antoine Ghestem1, Claude-Alain Maurage1,2, Annick Wattez1, Patrick Vermersch3 and André Delacourte1,+

1INSERM U422, Groupe VCDN, 1 place de Verdun, 59045 Lille Cedex, France, 2Service d’Anatomie et Cytologie pathologiques A and 3Service de Neurologie C, Hôpital Roger Salengro, (2–3), CHRU, Lille, France

Intraneuronal aggregates of hyperphosphorylated tau proteins, referred to as pathological tau, are found in brain areas of demented patients affected by numerous different neurodegenerative disorders. We previously described a particular biochemical profile of pathological tau proteins in myotonic dystrophy type 1 (DM1). This multisystemic disorder is characterized by an unstable CTG repeat expansion in the 3'-untranslated region of the DM protein kinase gene. In the human central nervous system, tau proteins consist of six isoforms that differ by the presence or absence of the alternatively spliced exons 2, 3 and 10. Here we show that the pattern of tau isoforms aggregated in DM1 brain lesions is characteristic. It consists mainly of the aggregation of the shortest human tau isoform. A disruption in normal tau isoform expression consisting of a reduced expression of tau isoforms containing the exon 2 was observed at both the mRNA and protein levels. Large expanded CTG repeats were detected and showed marked somatic heterogeneity between DM1 cases and in cortical brains regions analysed. Our data suggest a relationship between the CTG repeat expansion and the alteration of tau expression showing that DM1 is a peculiar tauopathy.

+ To whom correspondence should be addressed. Tel: +33 3 20 62 20 77; Fax: +33 3 20 62 20 79; Email: delacourte@lille.inserm.fr


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