Brain diseases
Mol Biol Cell. 2005 Jan;16(1):238-47.
Epub 2004 Oct 27. Pain. 2006 Jan;120(1-2):8-15. Epub 2005
Dec 20. J Neurosci. 2006 Jan 11;26(2):381-8. ·
J
Neurosci. 2006 Apr 26;26(17):4453-4. Proc
Natl Acad Sci U S A. 2005 Dec 20;102(51):18626-31.
Epub 2005 Dec 13. J Biol Chem. 2006 Apr 14;281(15):9919-24.
Epub 2006 Feb 7.
Cellular distribution and functions of
wild-type and constitutively activated Dictyostelium
PakB.
de
la Roche M, Mahasneh A, Lee
SF, Rivero F, Cote
GP.
Department of Biochemistry, Queen's University,
Dictyostelium PakB,
previously termed myosin I heavy chain kinase, is
a member of the p21-activated kinase (PAK)
family. Two-hybrid assays showed that PakB
interacts with Dictyostelium Rac1a/b/c, RacA (a RhoBTB protein), RacB, RacC, and RacF1.
Wild-type PakB displayed a cytosolic
distribution with a modest enrichment at the leading edge of migrating
cells and at macropinocytic and phagocytic cups, sites consistent with a role in
activating myosin I. PakB fused at the N terminus
to green fluorescent protein was proteolyzed in
cells, resulting in removal of the catalytic domain. C-terminal truncated PakB and activated PakB
lacking the p21-binding domain strongly localized to the cell cortex, to macropinocytic cups, to the posterior of migrating
cells, and to the cleavage furrow of dividing cells. These data indicate
that in its open, active state, the N terminus of PakB
forms a tight association with cortical actin
filaments. PakB-null cells displayed no
significant behavioral defects, but cells expressing activated PakB were unable to complete cytokinesis
when grown in suspension and exhibited increased rates of phagocytosis and pinocytosis.
PMID: 15509655 [PubMed - indexed for MEDLINE]
Mechanisms of placebo analgesia: rACC recruitment of a subcortical
antinociceptive network.
Bingel
U, Lorenz
J, Schoell
E, Weiller
C, Buchel
C.
NeuroImage Nord,
Institute for Systems Neuroscience,
Placebo analgesia is one of the most striking examples of the cognitive
modulation of pain perception and the underlying mechanisms are finally
beginning to be understood. According to pharmacological studies, the
endogenous opioid system is essential for placebo
analgesia. Recent functional imaging data provides evidence that the rostral anterior cingulate
cortex (rACC) represents a crucial cortical area
for this type of endogenous pain control. We therefore hypothesized that
placebo analgesia recruits other brain areas outside the rACC and that interactions of the rACC
with these brain areas mediate opioid-dependent
endogenous antinociception as part of a top-down
mechanism. Nineteen healthy subjects received and rated painful laser stimuli
to the dorsum of both hands, one of them treated with a fake analgesic
cream (placebo). Painful stimulation was preceded by an auditory cue,
indicating the side of the next laser stimulation. BOLD-responses to the
painful laser-stimulation during the placebo and no-placebo condition were
assessed using event-related fMRI. After having
confirmed placebo related activity in the rACC, a
connectivity analysis identified placebo dependent contributions of rACC activity with bilateral amygdalae
and the periaqueductal gray (PAG). This finding
supports the view that placebo analgesia depends on the enhanced functional
connectivity of the rACC with subcortical
brain structures that are crucial for conditioned learning and descending
inhibition of nociception.
Publication Types:
PMID: 16364549 [PubMed - indexed for MEDLINE]
Comment in:
Brain activity associated with
expectancy-enhanced placebo analgesia as measured by functional magnetic
resonance imaging.
Kong
J, Gollub
RL, Rosman
IS, Webb
JM, Vangel
MG, Kirsch
I, Kaptchuk
TJ.
Department of Psychiatry,
In this study, a well established expectancy manipulation model was
combined with a novel placebo intervention, a validated sham acupuncture
needle, to investigate the brain network involved in placebo analgesia. Sixteen
subjects completed the experiment. We found that after placebo acupuncture
treatment, subjective pain rating reduction (pre minus post) on the
placebo-treated side was significantly greater than on the control side.
When we calculated the contrast that subtracts the functional magnetic
resonance imaging (fMRI) signal difference
between post-treatment and pretreatment during pain application on placebo
side from the same difference on control side [e.g., placebo (post - pre) -
control (post - pre)], significant differences were observed in the
bilateral rostral anterior cingulate
cortex (rACC), lateral prefrontal cortex, right
anterior insula, supramarginal
gyrus, and left inferior parietal lobule. The
simple regression (correlation) analysis between each subject's fMRI signal difference of post-treatment and
pretreatment difference on placebo and control side and the corresponding
subjective pain rating difference showed that significant negative
correlation was observed in the bilateral lateral/orbital prefrontal
cortex, rACC, cerebellum, right fusiform, parahippocampus,
and pons. These results are different from a
previous study that found decreased activity in pain-sensitive regions such
as the thalamus, insula, and ACC when comparing
the response to noxious stimuli applied to control and placebo
cream-treated areas of the skin. Our results suggest that placebo analgesia
may be configured through multiple brain pathways and mechanisms.
PMID: 16407533 [PubMed - indexed for MEDLINE]
Control over brain activation and pain learned
by using real-time functional MRI.
deCharms
RC, Maeda
F, Glover
GH, Ludlow
D, Pauly
JM, Soneji
D, Gabrieli
JD, Mackey
SC.
Omneuron, Inc., 99 El Camino Real,
If an individual can learn to directly control activation of localized
regions within the brain, this approach might provide control over the neurophysiological mechanisms that mediate behavior and
cognition and could potentially provide a different route for treating
disease. Control over the endogenous pain modulatory
system is a particularly important target because it could enable a unique
mechanism for clinical control over pain. Here, we found that by using
real-time functional MRI (rtfMRI) to guide training,
subjects were able to learn to control activation in the rostral anterior cingulate
cortex (rACC), a region putatively involved in
pain perception and regulation. When subjects deliberately induced
increases or decreases in rACC fMRI activation, there was a corresponding change in
the perception of pain caused by an applied noxious thermal stimulus.
Control experiments demonstrated that this effect was not observed after
similar training conducted without rtfMRI
information, or using rtfMRI information derived
from a different brain region, or sham rtfMRI
information derived previously from a different subject. Chronic pain
patients were also trained to control activation in rACC
and reported decreases in the ongoing level of chronic pain after training.
These findings show that individuals can gain voluntary control over
activation in a specific brain region given appropriate training, that
voluntary control over activation in rACC leads
to control over pain perception, and that these effects were powerful
enough to impact severe, chronic clinical pain.
Publication Types:
PMID: 16352728 [PubMed - indexed for MEDLINE] 
The SUMO-Specific Protease SENP5 Is Required
for Cell Division.
Di
Bacco A, Ouyang
J, Lee
HY, Catic
A, Ploegh
H, Gill
G.
Department of Pathology,
Posttranslational modification of substrates by the small ubiquitin-like modifier, SUMO, regulates diverse
biological processes, including transcription, DNA repair, nucleocytoplasmic trafficking, and chromosome
segregation. SUMOylation is reversible, and
several mammalian homologs of the yeast
SUMO-specific protease Ulp1, termed SENPs, have
been identified. We demonstrate here that SENP5, a previously
uncharacterized Ulp1 homolog, has SUMO C-terminal hydrolase
and SUMO isopeptidase activities. In contrast to
other SENPs, the C-terminal catalytic domain of
SENP5 preferentially processed SUMO-3 compared to SUMO-1 precursors and
preferentially removed SUMO-2 and SUMO-3 from SUMO-modified RanGAP1 in
vitro. In cotransfection assays, SENP5
preferentially reduced high-molecular-weight conjugates of SUMO-2 compared
to SUMO-1 in vivo. Full-length SENP5 localized to the nucleolus. Deletion
of the noncatalytic N-terminal domain led to loss
of nucleolar localization and increased de-SUMOylation activity in vivo. Knockdown of SENP5 by RNA
interference resulted in increased levels of SUMO-1 and SUMO-2/3
conjugates, inhibition of cell proliferation, defects in nuclear
morphology, and appearance of binucleate cells,
revealing an essential role for SENP5 in mitosis and/or cytokinesis.
These findings establish SENP5 as a SUMO-specific protease required for
cell division and suggest that mechanisms involving both the catalytic and noncatalytic domains determine the distinct substrate
specificities of the mammalian SUMO-specific proteases.
Small ubiquitin-like
modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein.
Dorval V, Fraser
PE.
Department of Medical Biophysics and Centre for Research in Neurodegenerative
Diseases,
Sumoylation is an important post-translational
modification that provides a rapid and reversible means for controlling the
activity, subcellular localization, and stability
of target proteins. We have examined the covalent attachment of the small ubiquitin-like modifier (SUMO) proteins to tau and alpha-synuclein, two
natively unfolded proteins that define several neurodegenerative diseases.
Both brain proteins were preferentially modified by SUMO1, as compared with
SUMO2 or SUMO3. Tau contains two SUMO consensus
sequences, and mutational analyses identified