Specific tau variants in the brains of patients with myotonic dystrophy

Abstract

The mutation causing myotonic dystrophy (DM) is an unstable CTG trinucleotide repeat in a gene encoding for a protein with putative serine-threonine kinase activity. Several studies have reported the appearance of abnormally frequent neurofibrillary tangles (NFTs) in the cortex of patients with DM. Using immunologic probes against normal and pathologic hyperphosphorylated tau proteins, the basic components of NFTs, we performed a biochemical and immunohistochemical study of the brains of two DM cases. We compared the tau profiles with those found in Alzheimer's disease (AD) using mono- and two-dimensional immunoblotting. Patients were aged 53 and 61 years at death. In both cases, we observed few perikaryal and axonal inclusions in the hippocampus as well as the entorhinal and inferior temporal cortices. As in AD brain homogenates, pathologic tau proteins, named tau 55, 64, and 69, were exclusively immunodetected in the DM cases in the hippocampus, the entorhinal cortex, and in most of the temporal areas. Amounts of pathologic tau proteins were higher in the more severely affected case, but lower than in AD brain homogenates. Pathologic tau proteins were less acidic in DM than in AD. We found a very low amount of the tau 69 isoform in DM extracts, and in most of the cortical areas, tau 55 was overexpressed compared with AD homogenates. A link between the increase of kinase activity and the presence of pathologic tau proteins is discussed.

CELF6, a Member of the CELF Family of RNA-binding Proteins, Regulates Muscle-specific Splicing Enhancer-dependent Alternative Splicing

“…Alteration of the stoichiometry of tau isoforms contributes to the pathology of a number of neurodegenerative disorders (26). A pathological tau protein expression profile is seen in the brains of DM1 patients (27), mirrored by changes in tau pre-mRNA splicing (28). In transgenic mice carrying expanded CTG repeats in the context of the human DMPK region, tau expression profiles were similarly altered (29).…”

Misregulation of Alternative Splicing Causes Pathogenesis in Myotonic Dystrophy

“…Expression of human fetal tau isoforms in transgenic mice results in neurofibrillary tangles which are also seen in other neurological diseases (Andreadis 2005;Gotz et al 2001;Ishihara et al 2001). In addition, neurofibrillary tangles can be detected in brains of individuals with DM 1 (Kiuchi et al 1991;Vermersch et al 1996). These observations raise the possibility that expression of a fetal tau isoform might be involved in production of neurofibrillary tangles affecting behavioral and cognitive functions in individuals with DM 1.…”

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).…”