909 research outputs found
Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities
The discovery of the genetic causes of syndromic autism spectrum disorders and intellectual disabilities has greatly informed our understanding of the molecular pathways critical for normal synaptic function. The top-down approaches using human phenotypes and genetics helped identify causative genes and uncovered the broad spectrum of neuropsychiatric features that can result from various mutations in the same gene. Importantly, the human studies unveiled the exquisite sensitivity of cognitive function to precise levels of many diverse proteins. Bottom-up approaches applying molecular, biochemical, and neurophysiological studies to genetic models of these disorders revealed unsuspected pathogenic mechanisms and identified potential therapeutic targets. Moreover, studies in model organisms showed that symptoms of these devastating disorders can be reversed, which brings hope that affected individuals might benefit from interventions even after symptoms set in. Scientists predict that insights gained from studying these rare syndromic disorders will have an impact on the more common nonsyndromic autism and mild cognitive deficits
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Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice
Loss of function of the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2) causes the progressive neurological disorder Rett syndrome (RTT). Conversely, duplication or triplication of Xq28 causes an equally wide-ranging progressive neurological disorder, MECP2 duplication syndrome, whose features overlap somewhat with RTT. To understand which MeCP2 functions cause toxicity in the duplication syndrome, we generated mouse models expressing endogenous Mecp2 along with a RTT-causing mutation in either the methyl-CpG binding domain (MBD) or the transcriptional repression domain (TRD). We determined that both the MBD and TRD must function for doubling MeCP2 to be toxic. Mutating the MBD reproduces the null phenotype and expressing the TRD mutant produces milder RTT phenotypes, yet both mutations are harmless when expressed with endogenous Mecp2. Surprisingly, mutating the TRD is more detrimental than deleting the entire C-terminus, indicating a dominant-negative effect on MeCP2 function, likely due to the disruption of a basic cluster. DOI: http://dx.doi.org/10.7554/eLife.02676.00
Long XMM observation of the Narrow-Line Seyfert 1 galaxy IRAS13224-3809: rapid variability, high spin and a soft lag
Results are presented from a 500ks long XMM-Newton observation of the
Narrow-Line Seyfert 1 galaxy IRAS13224-3809. The source is rapidly variable on
timescales down to a few 100s. The spectrum shows strong broad Fe-K and L
emission features which are interpreted as arising from reflection from the
inner parts of an accretion disc around a rapidly spinning black hole. Assuming
a power-law emissivity for the reflected flux and that the innermost radius
corresponds to the innermost stable circular orbit, the black hole spin is
measured to be 0.988 with a statistical precision better than one per cent.
Systematic uncertainties are discussed. A soft X-ray lag of 100s confirms this
scenario. The bulk of the power-law continuum source is located at a radius of
2-3 gravitational radii.Comment: 7 pages, 14 figures, submitted to MNRA
Loss of MeCP2 in Parvalbumin-and Somatostatin-Expressing Neurons in Mice Leads to Distinct Rett Syndrome-like Phenotypes
SummaryInhibitory neurons are critical for proper brain function, and their dysfunction is implicated in several disorders, including autism, schizophrenia, and Rett syndrome. These neurons are heterogeneous, and it is unclear which subtypes contribute to specific neurological phenotypes. We deleted Mecp2, the mouse homolog of the gene that causes Rett syndrome, from the two most populous subtypes, parvalbumin-positive (PV+) and somatostatin-positive (SOM+) neurons. Loss of MeCP2 partially impairs the affected neuron, allowing us to assess the function of each subtype without profound disruption of neuronal circuitry. We found that mice lacking MeCP2 in either PV+ or SOM+ neurons have distinct, non-overlapping neurological features: mice lacking MeCP2 in PV+ neurons developed motor, sensory, memory, and social deficits, whereas those lacking MeCP2 in SOM+ neurons exhibited seizures and stereotypies. Our findings indicate that PV+ and SOM+ neurons contribute complementary aspects of the Rett phenotype and may have modular roles in regulating specific behaviors
Identification of a novel phosphorylation site in ataxin-1
AbstractSpinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease resulting from an expanded CAG repeat in the SCA1 gene that leads to an expanded polyglutamine tract in the gene product. Previous studies have demonstrated that serine at site 776 is phosphorylated [E.S. Emiamian, M.D. Kaytor, L.A. Duvick, T. Zu, S.K. Tousey, H.Y. Zoghbi, H.B. Clark, H.T. Orr, Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice, Neuron 38 (2003) 375-387.]. Studies of ataxin-1 S776 and serine mutated to an alanine, A776, have also shown differential protein–protein interactions and reduced neurodegeneration [H.K. Chen, P. Fernandez-Funez, S.F. Acevedo, Y.C. Lam, M.D. Kaytor, M.H. Fernandez, A. Aitken, E.M. Skoulakis, H.T. Orr, J. Botas, H.Y. Zoghbi, Interaction of Akt_phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1.]. However, mutation of the site serine 776 to an alanine did not abolish all phosphorylation of the protein ataxin-1, suggesting the presence of additional phosphorylation sites [E.S. Emiamian, M.D. Kaytor, L.A. Duvick, T. Zu, S.K. Tousey, H.Y. Zoghbi, H.B. Clark, H.T. Orr, Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice, Neuron 38 (2003) 375-387.]. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) and mutational analysis demonstrated a novel phosphorylation site at serine 239 of ataxin-1
Measuring Black Hole Spin using X-ray Reflection Spectroscopy
I review the current status of X-ray reflection (a.k.a. broad iron line)
based black hole spin measurements. This is a powerful technique that allows us
to measure robust black hole spins across the mass range, from the stellar-mass
black holes in X-ray binaries to the supermassive black holes in active
galactic nuclei. After describing the basic assumptions of this approach, I lay
out the detailed methodology focusing on "best practices" that have been found
necessary to obtain robust results. Reflecting my own biases, this review is
slanted towards a discussion of supermassive black hole (SMBH) spin in active
galactic nuclei (AGN). Pulling together all of the available XMM-Newton and
Suzaku results from the literature that satisfy objective quality control
criteria, it is clear that a large fraction of SMBHs are rapidly-spinning,
although there are tentative hints of a more slowly spinning population at high
(M>5*10^7Msun) and low (M<2*10^6Msun) mass. I also engage in a brief review of
the spins of stellar-mass black holes in X-ray binaries. In general,
reflection-based and continuum-fitting based spin measures are in agreement,
although there remain two objects (GROJ1655-40 and 4U1543-475) for which that
is not true. I end this review by discussing the exciting frontier of
relativistic reverberation, particularly the discovery of broad iron line
reverberation in XMM-Newton data for the Seyfert galaxies NGC4151, NGC7314 and
MCG-5-23-16. As well as confirming the basic paradigm of relativistic disk
reflection, this detection of reverberation demonstrates that future large-area
X-ray observatories such as LOFT will make tremendous progress in studies of
strong gravity using relativistic reverberation in AGN.Comment: 19 pages. To appear in proceedings of the ISSI-Bern workshop on "The
Physics of Accretion onto Black Holes" (8-12 Oct 2012). Revised version adds
a missing source to Table 1 and Fig.6 (IRAS13224-3809) and corrects the
referencing of the discovery of soft lags in 1H0707-495 (which were in fact
first reported in Fabian et al. 2009
Proprioceptor Pathway Development Is Dependent on MATH1
AbstractThe proprioceptive system provides continuous positional information on the limbs and body to the thalamus, cortex, pontine nucleus, and cerebellum. We showed previously that the basic helix-loop-helix transcription factor Math1 is essential for the development of certain components of the proprioceptive pathway, including inner-ear hair cells, cerebellar granule neurons, and the pontine nuclei. Here, we demonstrate that Math1 null embryos lack the D1 interneurons and that these interneurons give rise to a subset of proprioceptor interneurons and the spinocerebellar and cuneocerebellar tracts. We also identify three downstream genes of Math1 (Lh2A, Lh2B, and Barhl1) and establish that Math1 governs the development of multiple components of the proprioceptive pathway
Fast Spectral Variability from Cygnus X-1
We have developed an algorithm that, starting from the observed properties of
the X-ray spectrum and fast variability of an X-ray binary allows the
production of synthetic data reproducing observables such as power density
spectra and time lags, as well as their energy dependence. This allows to
reconstruct the variability of parameters of the energy spectrum and to reduce
substantially the effects of Poisson noise, allowing to study fast spectral
variations. We have applied the algorithm to Rossi X-ray Timing Explorer data
of the black-hole binary Cygnus X-1, fitting the energy spectrum with a
simplified power law model. We recovered the distribution of the power law
spectral indices on time-scales as low as 62 ms as being limited between 1.6
and 1.8. The index is positively correlated with the flux even on such
time-scales.Comment: 14 pages, 19 figures, accepted by MNRA
Math1 Is Essential for the Development of Hindbrain Neurons Critical for Perinatal Breathing
SummaryMice lacking the proneural transcription factor Math1 (Atoh1) lack multiple neurons of the proprioceptive and arousal systems and die shortly after birth from an apparent inability to initiate respiration. We sought to determine whether Math1 was necessary for the development of hindbrain nuclei involved in respiratory rhythm generation, such as the parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN), defects in which are associated with congenital central hypoventilation syndrome (CCHS). We generated a Math1-GFP fusion allele to trace the development of Math1-expressing pFRG/RTN and paratrigeminal neurons and found that loss of Math1 did indeed disrupt their migration and differentiation. We also identified Math1-dependent neurons and their projections near the pre-Bötzinger complex, a structure critical for respiratory rhythmogenesis, and found that glutamatergic modulation reestablished a rhythm in the absence of Math1. This study identifies Math1-dependent neurons that are critical for perinatal breathing that may link proprioception and arousal with respiration
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