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

Intraneuronal aggregates of hyperphosphorylated tau proteins, referred to a s 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 d ystrophy type 1 (DM1). This multisystemic disorder is characterized by an u nstable CTG repeat expansion in the 3'-untranslated region of the DM protei n kinase gene. In the human central nervous system, tau proteins consist of six isoforms that differ by the presence or absence of the alternatively s pliced exons 2, 3 and 10. Here we show that the pattern of tau isoforms agg regated in DM1 brain lesions is characteristic. It consists mainly of the a ggregation of the shortest human tau isoform. A disruption in normal tau is oform expression consisting of a reduced expression of tau isoforms contain ing the exon 2 was observed at both the mRNA and protein levels. Large expa nded CTG repeats were detected and showed marked somatic heterogeneity betw een DM1 cases and in cortical brains regions analysed. Our data suggest a r elationship between the CTG repeat expansion and the alteration of tau expr ession showing that DM1 is a peculiar tauopathy.