55 research outputs found
The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome
Recent studies have reported that alleles in the premutation range in the
FMR1 gene in males result in increased FMR1 mRNA levels and at the same
time mildly reduced FMR1 protein levels. Some elderly males with
premutations exhibit an unique neurodegenerative syndrome characterized by
progressive intention tremor and ataxia. We describe neurohistological,
biochemical and molecular studies of the brains of mice with an expanded
CGG repeat and report elevated Fmr1 mRNA levels and intranuclear
inclusions with ubiquitin, Hsp40 and the 20S catalytic core complex of the
proteasome as constituents. An increase was observed of both the number
and the size of the inclusions during the course of life, which correlates
with the progressive character of the cerebellar tremor/ataxia syndrome in
humans. The observations in expanded-repeat mice support a direct role of
the Fmr1 gene, by either CGG expansion per se or by mRNA level, in the
formation of the inclusions and suggest a correlation between the presence
of intranuclear inclusions in distinct regions of the brain and the
clinical features in symptomatic premutation carriers. This mouse model
will facilitate the possibilities to perform studies at the molecular
level from onset of symptoms until the final stage of the disease
The Persistence Length of a Strongly Charged, Rod-like, Polyelectrolyte in the Presence of Salt
The persistence length of a single, intrinsically rigid polyelectrolyte
chain, above the Manning condensation threshold is investigated theoretically
in presence of added salt. Using a loop expansion method, the partition
function is consistently calculated, taking into account corrections to
mean-field theory. Within a mean-field approximation, the well-known results of
Odijk, Skolnick and Fixman are reproduced. Beyond mean-field, it is found that
density correlations between counterions and thermal fluctuations reduce the
stiffness of the chain, indicating an effective attraction between monomers for
highly charged chains and multivalent counterions. This attraction results in a
possible mechanical instability (collapse), alluding to the phenomenon of DNA
condensation. In addition, we find that more counterions condense on slightly
bent conformations of the chain than predicted by the Manning model for the
case of an infinite cylinder. Finally, our results are compared with previous
models and experiments.Comment: 13 pages, 2 ps figure
Astroglial-targeted expression of the fragile X CGG repeat premutation in mice yields RAN translation, motor deficits and possible evidence for cell-to-cell propagation of FXTAS pathology
The fragile X premutation is a CGG trinucleotide repeat expansion between 55 and 200 repeats in the 5′-
untranslated region of the fragile X mental retardation 1 (FMR1) gene. Human carriers of the premutation
allele are at risk of developing the late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia
syndrome (FXTAS). Characteristic neuropathology associated with FXTAS includes intranuclear inclusions in
neurons and astroglia. Previous studies recapitulated these histopathological features in neurons in a knock-in
mouse model, but without significant astroglial pathology. To determine the role of astroglia in FXTAS, we
generated a transgenic mouse line (Gfa2-CGG99-eGFP) that selectively expresses a 99-CGG repeat expansion
linked to an enhanced green fluorescent protein (eGFP) reporter in astroglia throughout the brain, including
cerebellar Bergmann glia. Behaviorally these mice displayed impaired motor performance on the ladder-rung
test, but paradoxically better performance on the rotarod. Immunocytochemical analysis revealed that CGG99-
eGFP co-localized with GFAP and S-100ß, but not with NeuN, Iba1, or MBP, indicating that CGG99-eGFP
expression is specific to astroglia. Ubiquitin-positive intranuclear inclusions were found in eGFP-expressing glia
throughout the brain. In addition, intracytoplasmic ubiquitin-positive inclusions were found outside the nucleus in
distal astrocyte processes. Intriguingly, intranuclear inclusions, in the absence of eGFP mRNA and eGFP fluorescence,
were present in neurons of the hypothalamus and neocortex. Furthermore, intranuclear inclusions in both neurons and
astrocytes displayed immunofluorescent labeling for the polyglycine peptide FMRpolyG, implicating FMRpolyG in the
pathology found in Gfa2-CGG99 mice. Considered together, these results show that Gfa2-CGG99 expression in mice is
sufficient to induce key features of FXTAS pathology, including formation of intranuclear inclusions, translation of
FMRpolyG, and deficits in motor function
Micromechanics of Single Supercoiled DNA Molecules
Abstract. The theory of the mechanical response of single DNA molecules un-der stretching and twisting stresses is reviewed. Using established results for the the semiflexible polymer including the effect of torsional stress, and for the free energy of plectonemic supercoils, a theory of coexisting plectonemic and extended DNA is con-structed and shown to produce phenomena observed experimentally. Analytical results for DNA extension and torque are presented, and effects of anharmonicities in the plec-tonemic free energy are described. An application of the theory to the problem of torsional-stress-induced cruciform extrusion is also discussed. Key words. DNA, molecular biology, statistical mechanics, polymer physics. AMS(MOS) subject classifications. 82D60, 92C05, 92C40
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