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1566iti Page 938 Thursday, March 7, 2002 2:30 PM
Published March 18, 2002
In This Issue
Finding the dark side of tau
APP transport (top)
is inhibited by
excess tau protein
(bottom).
view is that tau
stabilizes microtubules, and
disease results when the protein
detaches from microtubules and
aggregates into paired helical
filaments. According to the authors,
the opposite situation—having too
much tau attached to microtubules—
may be just as bad.
Overexpressing tau in neuroblastoma
cell lines, primary hippocampal
neurons, or retinal ganglion cells
leaves microtubules intact. Rather
than forming filaments, the
overexpressed tau binds to
microtubules and appears to lay
the groundwork for neurodegeneration.
Excess tau causes the depletion
of mitochondria and peroxisomes
from the cells’ processes, retarding
growth and increasing the cells’
sensitivity to oxidative stress. The
transport of Golgi-derived vesicles
into axons is inhibited, and
neurofilament proteins and vesicles
carrying the amyloid precursor
protein (APP) accumulate in the
cell body. These changes are likely
to increase the production of toxic
amyloid A peptides, a hallmark of
Alzheimer’s disease.
Thus, whereas low levels of tau
are necessary for microtubule
stability, higher levels interfere
with transport. Detachment of tau
from microtubules and aggregation
of tau into filaments might be a
later consequence of the trafficking
problems caused by excess tau
attaching to microtubules. The
results also suggest a novel regulatory
system for microtubule-based
motors, in which tau and other
proteins on microtubules might
act as roadblocks that determine
the rate of vesicle trafficking. Tubulin but not microtubule
T
he pathogens that cause malaria,
composed of tubulin protofilaments,
cryptosporidiosis, and toxoplasmosis
supporting the microtubule hypothesis.
share a baffling common feature: a
But careful ultrastructural analysis
cone-shaped apical structure called the
shows that the tubulin in the conoid
conoid. Previous research has suggested
assembles in a manner never before
that the conoid is composed of
observed, creating a structure with
microtubules and has simultaneously
a comma-shaped cross section rather
provided evidence that it is not. Now,
than a microtubule. Previously
on page 1039, Hu et al. resolve this
described tubulin structures are
longstanding dilemma by demonstrating
generally circular or semicircular in
that the conoid is made of tubulin, but
cross section.
not in the form of classical microtubules.
Hu et al. also found that the conoid
In addition to describing a previously
fibers are assembled rapidly during the
unknown form of cytoskeletal structure,
early phases of cell division. The flattened
the results could help in the development
cross section explains how tubulin can
Conoids consist of tubulin in an
of new treatments for some of the
conform to the tight bends found in the
unconventional arrangement.
world’s most devastating diseases.
conoid—a ribbon is easier to bend than
The conoid is part of the apical
a straw—but more work will be needed
complex, the defining feature of the phylum Apicomplexa and
to understand how the cell directs the assembly of this novel
a structure thought to be involved in host cell invasion by
structure, and how the increased pitch of the fibers and the
these parasites. Although tubulin was considered the most
translation of the entire structure contribute to the spring-like
likely building block of the conoid, the bends in the structure
action of the conoid. The conoid’s unique architecture makes
appeared too tight to be accommodated by microtubules.
it an attractive drug target, especially since parasite and host
Combining transgenic Toxoplasma gondii and an array of
microtubules are known to differ in their sensitivity to various
imaging techniques, the authors confirmed that the conoid is
compounds. 938 The Journal of Cell Biology | Volume 156, Number 6, 2002
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n page 1051,
Stamer et al.
have uncovered
what may be a critical early step in
the pathogenesis
of Alzheimer’s
disease and
a previously
unappreciated
regulatory system
for microtubulebased motors. The
work focuses on
the microtubuleassociated protein
tau, which is
thought to cause
the pathological
changes seen in
some neurodegenerative diseases.
The prevailing
O
1566iti Page 939 Thursday, March 7, 2002 2:30 PM
Published March 18, 2002
TEXT BY ALAN W. DOVE
[email protected]
Only one way to
skin a mouse
T
he actin cytoskeleton is a highly
adaptable framework. In some
structures actin polymerizes and
depolymerizes rapidly to facilitate
quick movement, whereas in others
actin monomers turn over quite slowly
to maintain structural integrity. On
page 1065, Ono and Ono show that
competition between two actin-binding
proteins, ADF/cofilin and tropomyosin,
determines the stability of actin thin
filaments in C. elegans muscle.
An acid invasion
I
ntracellular parasites must walk a
pH. By amino acid substitution, the
fine line, invading and exploiting
authors determined that changing a
a host cell without killing it too
single residue largely relieves this
quickly. On page 1029, Glomski et
pH dependence, but bacteria
al. show how a single amino acid
expressing the pH-independent
determines not only the pH
form of the enzyme are 100-fold less
optimum of a bacterial
virulent in mice. The
hemolysin, but also the
virulence defect is not
virulence of an important
in cellular entry. The
pathogen. The data
mutants escape from
help explain how
acidified phagosomes,
Listeria monocytogenes
grow in the cytosol,
distinguishes between
and spread from cell
the membranes of
to cell. But bacteria
acidic vesicles, which
expressing the mutant
the bacterium must
LLO permeabilize the
pierce to enter the
host cell membrane
cytosol, and the plasma
prematurely. The
membrane, which
authors propose that
A single residue determust remain intact
the acidic pH optimum
mines acid sensitivity in
while the parasite
of LLO is an adaptation
a bacterial hemolysin.
reproduces.
to the parasitic lifestyle,
The activity of the L. monocytogenes
allowing Listeria to penetrate acidic
pore-forming hemolysin listeriolysin
vesicles while leaving the plasma
O (LLO) is strongly induced by low
membrane intact. Actin (green) and ADF/cofilin (red) are
disorganized in the absence of tropomyosin
(bottom).
Previously, the authors found that
worms with mutations in a muscle-specific
ADF/cofilin isoform could not assemble
normal myofibrils. ADF/cofilin appears
to increase actin turnover, but myofibrils
are highly stable structures, suggesting
that some additional factor must inhibit
ADF/cofilin in order to stabilize the
myofibrils. The new study demonstrates
that purified tropomyosin and ADF/cofilin
compete for binding to purified F-actin,
and that ADF/cofilin cannot bind to
isolated myofibrils unless the attached
tropomyosin is removed from the
myofibrils first. RNAi suppression
of tropomyosin disrupts myofibril
organization in wild-type worms, but
not in ADF/cofilin mutant worms.
The results suggest that in vivo
tropomyosin preserves myofilaments
by blocking the destabilizing effects
of ADF/cofilin. In This Issue 939
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t isn’t often that textbooks have
to be revised because of a single
research paper, but that appears to
be the case for the work described
by Furuse et al. on page 1099. The
standard view of epithelial structure
is that continuous tight junctions
(TJs) are required only in simple
epithelia like those that separate
internal organs, but are not found
Tight junctions have turned up in the epidermis.
in stratified epithelia like the
epidermis. The authors’ analysis of mice lacking the TJ component claudin-1,
however, shows that TJs are indeed found in the skin and are at least as necessary
there as in simple epithelia.
Claudin-1 belongs to a multigene family that contributes to the backbone of TJ
strands, so its deletion should affect simple epithelia. Surprisingly, the major defect
in claudin-1–deficient mice is lethally leaky skin: the mice are born normally but
die within a day, apparently from dehydration. Permeability assays of the claudin-1–
deficient skin show excessive water loss.
In contrast with previous reports, Furuse et al. found continuous TJs in the stratum
granulosum, a subset of the epidermis, of both wild-type and mutant mice. The
results suggest that functional TJs are required in both types of epithelia and that
loss of claudin-1 increases the permeability of the epidermal TJs without disrupting
the organization of the keratinocytes. I
Tropomyosin keeps
actin tough