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

Abstract

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.

Tau Monoclonal Antibody Generation Based on Humanized Yeast Models

“…M19G) or the C terminus of protein Tau (i.e. TauCter) (34). As shown, the study clearly confirmed the accumulation of Tau monomeric isoforms and the 130-kDa oligomers in the lipid raft enriched fractions (Fig.…”

Cloning and embryonic expression patterns of the chicken CELF family

“…Several neuronal targets of the vertebrate CELF proteins have been identified, including the N-methyl D-aspartate receptor 1 (NMDA R1), amyloid beta precursor protein (APP), and the microtubule associated protein tau (Poleev et al, 2000;Zhang et al, 2002;Wang et al, 2004;Han and Cooper, 2005;Leroy et al, 2006). Misregulated alternative splicing of these transcripts is thought to contribute to the CNS symptoms of patients with myotonic dystrophy (Vermesch et al, 1996;Sergeant et al, 2001;Jiang et al, 2004;Maurage et al, 2005), a multisystemic disorder in which elevated CELF activity has been linked directly to splicing changes that cause disease symptoms in skeletal muscle (Savkur et al, 2001;Charlet-B. et al, 2002b).…”

Ribonuclear foci at the neuromuscular junction in myotonic dystrophy type 1

“…The pattern of tau splice products expressed in adult DM1 brain is similar to that normally expressed in fetal brain [22,25], which may contribute to the development of neurofibrillary tangles and hyperphosphorylated tau in DM1 [26]. It is noteworthy that forced expression of fetal tau in motor neurons of transgenic mice led to motor axonopathy and muscle wasting [27].…”