Myotonic dystrophy (Steinert disease)
a disease with an abnormal splicing of numerous proteins, including Tau
Biochemical signature of abnormal tau proteins in the brain of DM1 patients
In some brains areas, aggregated tau proteins are found in degenerating
An abnormal profile of normal tau is observed in all brain areas.
Myotonic dystrophy type 1 (DM1) is a dominantly inherited multisystemic
disorder caused by unstable expansion of CTG trinucleotide repeats in a gene
encoding a serine/threonine protein kinase, named DMPK . The normal allele is
polymorphic, ranging from 5 to 35 CTG repeats whereas in DM1 the pathologic
allele expands from 50 to multiple thousands of CTG repeats. Expansion of the
CTG repeat is correlated with the disease severity and with the anticipation of
the age of onset . The clinical expression of DM1 is extremely variable and
includes myotonia and progressive muscle weakness, frontal baldness, cataract,
cardiac conduction defects, hypogonadism, endocrine deficiency and mental
Neurofibrillary tangles (NFT) in the neocortex and in subcortical nuclei of
DM1 patients have been described in several studies . NFT, as described in
Alzheimer's disease, consists of intraneuronal accumulation of paired helical
filaments (PHF) . They result from the aggregation of hyperphosphorylated
microtubule-associated tau proteins , referred to as PHF-tau or pathological tau
Tau protein belongs to the family of microtubule-associated proteins . They
are essentially expressed in neurons where their essential function is to
regulate the microtubule network. In the adult human brain, alternative splicing
of exons 2, 3 and 10 of the single tau gene transcript gives six tau isoforms
(Fig. 1A). Mutations in the tau gene are responsible for Frontotemporal dementia
with Parkinsonism linked to chromosome 17 (FTDP-17) . The mutations are
distributed over exons 9 to 13 and in the introns flanking the exon 10. These
mutations lead to alteration of tau protein binding to microtubule or affect the
post-transcriptional maturation of tau pre-mRNA and thus changing the tau
isoform stoichiometry of expression .
Yet, tau pathology is observed in 22 neurodegenerative disorders merged as
tauopathies . Four tauopathy classes are distinguishable by the tau protein
isoforms that constitute the specific pathological tau electrophoretic profile .
Thus, in AD the six isoforms determine the pathological tau triplet at 60, 64
and 69 kDa and the minor 74 kDa component (Class 1) . Tau isoforms containing
the exon 10 compose the pathological tau doublet at 64 and 69 kDa (Class 2) that
is observed in PSP and corticobasal degeneration (CBD) . The tau isoforms
lacking the exon 10 constitute the typical doublet at 60 and 64 kDa of Pick’s
disease (PiD) (Class 3) . Depending on the tau gene mutation, FTDP-17
pathological tau patterns belong to classes 1 to 3 . In contrast, the
pathological tau profile of class 4 is characterized by a major 60 kDa
component, a 64 kDa and minor 69 kDa component. It is restricted to DM1 . These
data suggest that specific sets of isoforms are expressed in particular subsets
of neurons selectively affected according to the neurodegenerative disorder .
Upon multiple molecular mechanism hypotheses, recent data suggest that the
expanded CUG repeat in the 3’ UTR of the DMPK mRNA act as a gain-of-function
mutation by sequestering RNA binding proteins, leading to depletion of
transcripts that require these protein for normal gene expression . The specific
pathological tau pattern observed in DM1 suggests that a specific set of tau
protein isoforms is implicated in this neurodegenerative disorder . Our results
suggest that the (CTG)n expansion is altering the processing of tau
pre-mRNA splicing, leading to a change in tau protein isoforms expression.
- Dysregulation of human brain microtubule-associated tau mRNA maturation in
myotonic dystrophy type 1.
Hum Mol Genet. 2001 Sep 15;10(19):2143-55.
- reprint of
the HMG paper
Seznec H, Agbulut O, Sergeant N, Savouret C, Ghestem A, Tabti N, Willer
JC, Ourth L, Duros C, Brisson E, Fouquet C, Butler-Browne G, Delacourte
A, Junien C, Gourdon G.
transgenic for the human myotonic dystrophy region with expanded CTG repeats
display muscular and brain abnormalities.
Hum Mol Genet. 2001 Nov 1;10(23):2717-26.