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Regular Articles |
¶
From the Departments of Laboratory Medicine and
Pathology;*
Genetics, Cell Biology, and
Development;
Biochemistry, Molecular Biology,
and Biophysics;
and the Institute of Human
Genetics,¶
University of Minnesota, Minneapolis,
Minnesota; and the Department of Molecular and Human
Genetics,
Howard Hughes Medical Institute,
Baylor College of Medicine, Houston, Texas
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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1/2, GluR2/3, and protein
kinase C (PKC) 
. Further examination of PKC revealed that its
sequestration into cytoplasmic vacuoles was accompanied by concurrent
loss of PKC localization at the Purkinje cell dendritic membrane and
decreased detection of PKC by Western blot analysis. In
addition, the vacuoles were immunoreactive for components of
the ubiquitin/proteasome degradative pathway. These findings present a
link between vacuole formation and loss of dendrites in Purkinje cells
of SCA1 mice and indicate that altered somatodendritic
membrane trafficking and loss of proteins including PKC, are
a part of the neuronal dysfunction in SCA1 transgenic
mice.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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By overexpressing a full-length SCA1 cDNA-encoding mutant ataxin-1 with 82 glutamines under the direction of the Purkinje cell-specific Pcp2/L7 promoter, we established transgenic mice that develop a progressive ataxia.3,4 These SCA1 transgenic mice have provided several important insights into the molecular basis of this polyglutamine-induced disease. In these mice, before the onset of ataxia, multiple pathological alterations were detected in Purkinje cells. At 3 weeks of age, large vacuoles were detected in the cell bodies of many Purkinje cells.3,4 Electron micrographs of the vacuoles revealed that they were membrane-bound, frequently multivesicular, and had a clear lumen.4 At 4 weeks of age, single large intranuclear aggregates containing mutant ataxin-1 were detected in a subset of Purkinje cells.5 The percentage of Purkinje cells that contained a large ataxin-1 aggregate increased throughout time, such that by 12 weeks of age 90% of the cells contained an aggregate.5 Also by 4 weeks of age many of the Purkinje cells had eccentric nucleoli.5 By 5 weeks of age, a loss of proximal dendrites and shrinkage of the molecular layer became evident (P.J. Skinner, University of Minnesota, unpublished data).4 By 6 weeks of age, the nuclei of many Purkinje cells were severely invaginated,6 and by 8 weeks of age, mild gliosis was detected in the molecular layer.4 After the onset of ataxia, which is first detectable at 12 weeks of age, heterotopic Purkinje cells become detectable in the molecular layer of the cerebellum.4,6 At 24 weeks of age, Purkinje cell loss became evident.4 Thus, significant neuropathology develops in the Purkinje cells of SCA1 transgenic mice before the onset of ataxia. Furthermore, the onset of ataxia occurs before there is detectable loss of Purkinje cells.
Transgenic mice expressing a variant form of mutant ataxin-1 with a nonfunctional nuclear localization signal revealed that mutant ataxin-1 has to enter the nucleus of a Purkinje cell to cause disease.6 In another series of SCA1 transgenic mice, a form of mutant ataxin-1 lacking a portion of its self-association region was expressed in Purkinje cells. These mice developed disease in the absence of detectable nuclear aggregates despite nuclear expression of ataxin-1.6 Thus, although the localization of mutant ataxin-1 to the nucleus is required for disease, the formation of nuclear aggregates of ataxin-1 is not.
Recently, Lin and colleagues7 used a PCR-based subtractive cDNA cloning approach and demonstrated that mutant ataxin-1, very early in the disease process, induces alterations in gene expression in both SCA1 transgenic mice and SCA1 patients. This altered expression of genes likely contributes to the neuropathological alterations and eventual dysfunction of the Purkinje cells.
The coexistence of cytoplasmic vacuoles and dendritic atrophy in the Purkinje cells of SCA1 transgenic mice raises the possibility that these two pathological features are in some way related. To investigate this hypothesis, we examined the subcellular distribution of somatodendritic membrane proteins in Purkinje cells of SCA1 mice. The results clearly indicated that the cytoplasmic vacuoles contain proteins typically located in the somatodendritic membrane, supporting the idea that the vacuoles are derived from the somatodendritic membrane of Purkinje cells. Moreover, the localization of components of the ubiquitin-proteasomal pathway (UPP) to the vacuoles suggested that the vacuoles are a site of protein degradation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Sections were generated and stained as described.5
Mice were anesthetized and perfused with phosphate-buffered saline
(PBS)-buffered formalin. The brains were immersed in PBS-buffered
formalin and further fixed overnight, transferred to PBS, and stored at
4°C. Fifty-µm vibratome sections were cut from the midline sagittal
plane of cerebella. Free-floating sections were blocked overnight with
2% normal goat serum in PBS with 0.3% Triton X-100 and then incubated
with primary antibodies in blocking solution for 2 days on a rocker at
4°C. Sections were washed with PBS four times, for at least 20
minutes, and incubated in secondary antibodies in blocking solution for
2 days on a rocker at 4°C. Sections were washed with PBS four times
for at least 20 minutes, and mounted on slides using glycerol-gelatin
(Sigma Chemical Co., St. Louis, MO) containing 4 mg/ml n-propylgalate.
Antibodies used were: a monoclonal anti-calbindin CL300 (1:500; Sigma)
and a polyclonal anti-calbindin D-28 antibody (1:500; Chemicon,
Temecula, CA), a rabbit anti-protein kinase C (PKC) antibody
(1:1000, Sigma), a rabbit anti-20S proteasome core antibody (1:1000,
Afiniti), and an anti-ubiquitin (DAKO, Carpinteria, CA). Goat
anti-rabbit and anti-mouse antibodies conjugated to either Cy2 or Cy3
(1:500; Jackson ImmunoResearch, West Grove, PA), or goat anti-mouse
antibodies conjugated to Alexa 488 (1:500; Molecular Probes, Eugene,
OR) were used as secondary antibodies. Sections were analyzed using a
BioRad MRC 1000 confocal microscope (Bio-Rad, Richmond, CA). Images
were processed using Confocal Assistant and Adobe Photoshop.
Immunohistochemical Staining of Mouse Cerebellum
Immunohistochemistry was performed on 40-mm cryostat or vibratome sections from formalin-perfused brains that were soaked overnight in 20% buffered sucrose before sectioning. For mGluR1, staining was performed using the ABC Elite kit (Vector Laboratories, Burlingame, CA): sections were blocked for 1 hour in normal serum, incubated overnight at room temperature (mGlur1, 1:500), washed four times for 5 minutes each in PBS, and incubated for 2 hours at room temperature with biotinylated anti-mouse antibodies (1:200). These were washed four times for 5 minutes in PBS, incubated for 1 hour with avidin-biotin-peroxidase complex reagent, washed 2 times for 5 minutes in PBS, and two times for 5 minutes each in Tris, pH 7.6, exposed for several minutes to diaminobenzidine substrate, washed four times for 5 minutes each in PBS, dehydrated, cleared, and mounted.
RNA and Protein Analysis
For Northern blot analysis, cerebellar RNA was isolated by the
acid guanidinium thiocyanate-phenol/chloroform method,8
electrophoresed in the presence of glyoxal, blotted, and probed with
radiolabeled cDNAs. For Western blot analysis, cerebella were
homogenized in lysis buffer (10% glycerol, 5% mercaptoethanol, 2.3%
sodium dodecyl sulfate, 0.06 mol/L Tris, pH 6.8). A portion of the
crude lysate was heated with loading buffer and electrophoresed,
blotted, and probed with rabbit anti- PKC (1:1000) or preimmune
serum (1:1000), all with 0.1% Tween-20. After incubating with
anti-rabbit or anti-mouse horseradish peroxidase conjugate, bands were
visualized by chemiluminescence (NEN Renaissance kit; Dupont-New
England Nuclear, Boston, MA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Electron microscopic analysis revealed that the cytoplasmic
vacuoles were distended membranous structures.9
Confocal
microscopic analyses of the cytoplasmic vacuoles in SCA1
transgenic Purkinje cells revealed that in some Purkinje cells, the
vacuoles seemed to be contiguous with the outer membrane (Figure 1)
. This observation indicated that the
cytoplasmic vacuoles are formed by the internalization of a substantial
portion of the plasma membrane.
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shows that the vacuole in a
SCA1 Purkinje cell stained strongly with wheat germ
agglutinin (WGA), as well as the outer membranes of many cells in the
cerebellar cortex. The WGA was typically found associated with membrane
of the vacuoles as indicated in Figure 2A
, but was also occasionally
found as a bright focus within the lumen of vacuoles. The vacuoles were
found not to be reactive to concanavalin A, an endoplasmic reticulum
marker, and were not stained by antibodies to cathepsin D, a lysosomal
marker, antibodies to the p58 Golgi protein, or markers to
multivesicular vesicles (data not presented). From these data, it was
concluded that the vacuoles were likely derived from the
somatodendritic membrane.
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shows that a
vacuole present in a 9-week-old B05/+ SCA1
Purkinje cell was immunoreactive for mGluR1. Within the vacuoles,
the mGluR1 staining was present in multiple small, typically less than
0.5-µm aggregates that primarily associated with the vacuolar
membrane. In addition, the vacuoles were found to be immunoreactive for
the dendritic membrane proteins GluR1/2 (Figure 2C)
and for
GluR2/3 (Figure 2D)
. The staining of GluR1/2 (Figure 2C)
, and
GluR2/3 was typically found in 1 µm in diameter or smaller aggregates
and these aggregates were found both associated with the vacuole
membrane as well as within the lumen of the vacuoles. Thus, by
immunolocalization analyses the cytoplasmic vacuoles in B05/+ Purkinje
cells contained several proteins and markers typically found in the
somatodendritic membrane compartment. Therefore, the cytoplasmic
vacuoles are very likely derived from the somatodendritic membrane.
Distribution of Membrane-Associated PKC in Transgenic SCA1
Purkinje Cells
PKC is expressed highly within Purkinje cells in the cerebellar
cortex.11
Because the translocation of PKC to the cell
membrane is associated with its activation,12-14
we were
interested in determining the subcellular distribution of the PKC in
SCA1 Purkinje cells, particularly its membrane-associated
form. Sections from 10-week-old wild-type and B05/+ SCA1
animals were examined by confocal microscopy after immunofluorescence
staining of the Purkinje cell-specific protein calbindin and PKC.
Figure 3A
shows the robust dendritic tree
of a 10-week-old wild-type Purkinje cell. The substantial atrophy of
the dendritic tree is revealed by calbindin immunoreactivity in a B05/+
10-week-old Purkinje cell (Figure 3B)
. In a wild-type Purkinje cell,
PKC was localized to the cytoplasm of the Purkinje cell body and to
the membrane of the primary and secondary dendrites throughout the
extent of the dendritic tree (Figure 3C)
. In contrast to the
distribution of PKC in wild-type murine Purkinje cells, by 10 weeks
of age in B05/+ Purkinje cells, PKC expression was limited to the
somatic membrane and did not extend into the dendritic tree (Figure 3
;
D–F). In addition, the cytoplasmic vacuoles were strongly
immunoreactive for PKC. Within the vacuoles, PKC was typically
associated with the membrane as indicated in Figure 3F
. However, in
some vacuoles, PKC was aggregated in the lumen of the vacuole and
not associated with the membrane (data not shown).
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expression
with disease progression in B05/+ SCA1 Purkinje cells,
cerebellar sections were examined by immunofluorescence at various ages
(Figure 4)
. In wild-type Purkinje cells
at 3 weeks of age (Figure 4A)
, at 10 weeks of age (Figure 4C)
, and at
13 weeks of age (Figure 4E)
PKC was localized to the
dendritic membranes. However, as early as 3 weeks of age, well before
the development of ataxia,4
B05/+ Purkinje cells had a
discernible loss of membrane-associated PKC expression in the
dendrites (Figure 4B)
. Thus, early in the disease process of
SCA1 mice, before the onset of ataxia, PKC normally found
associated with the dendritic membrane was found associated with the
somatodendritic membrane and internalized in cytoplasmic vacuoles.
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Because the cytoplasmic vacuoles of B05/+ SCA1 Purkinje
cells contained proteins typically found in the somatodendritic
membrane, we reasoned that their formation might be related to the loss
of the dendritic tree and, thus, might contain components of a
protein-degradative pathway. One protein-degradative pathway that has a
role in the pathological response to the expression of an expanded
SCA1 allele is the UPP.15
At 5 weeks of age,
all of the cytoplasmic vacuoles in B05/+ Purkinje cells were intensely
immunoreactive for ubiquitin (Figure 5A)
.
The ubiquitin immunoreactivity was found in large, 0.5 to 4 µm in
diameter aggregates within the vacuoles. By 10 weeks, only 50% of the
vacuoles were immunoreactive for ubiquitin and the staining was less
intense (Figure 5B)
. Perhaps reflecting the degradation of the
ubiquitinated proteins in the vacuoles. Therefore, we next ascertained
whether the proteasome apparatus also localized to the
ubiquitin-positive vacuoles. Figure 5, C and D
, shows that B05/+
cytoplasmic vacuoles were immunoreactive for the anti-20S proteasome.
The proteasome staining showed multiple small, less that 0.5 µm in
diameter, aggregates around the periphery of each vacuole. The size and
abundance of the proteasome aggregates was increased in sections from a
10-week-old animal (Figure 5D)
compared to sections from a 5-week-old
animal (Figure 5C)
. Thus, the proteins located within the cytoplasmic
vacuoles may be undergoing ubiquitin-mediated degradation.
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Was Primarily because of Protein Degradation
To gain insight into a molecular basis for the loss of PKC in
SCA1 transgenic cerebella, Western and Northern blot
analyses were performed. Figure 6A
shows
that in B05/+ mice at 3 weeks of age, relative to wild-type cerebellum,
there was a slight decrease in the amount of PKC protein detectable
by Western blot analysis. Thus, early on the primary change seen in
PKC expression was a redistribution from the dendritic membrane to
the Purkinje cell body (Figure 4B)
. However, as the SCA1
mice aged there was a detectable loss in absolute levels of PKC mRNA
and more notably PKC protein. By 13 weeks of age the level of PKC
protein was barely detectable (Figure 6A)
. Importantly, although
Northern blot analyses at 3 and 12 weeks of age (Figure 6C)
showed a
slight decrease in PKC mRNA, the magnitude of this change is
insufficient to explain the profound decrease in PKC protein shown
by Western blotting. Thus, the loss in PKC mRNA was considerably
less than the changes seen at the protein level. These data indicate
that a substantial proportion of the loss of PKC protein in B05/+
Purkinje cells is the result of a posttranscription mechanism, such as
an increase in protein turnover.
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Because we found that PKC protein levels decreased dramatically
in the SCA1 mouse Purkinje cells, we thought it would be
important to determine the specificity of this change. As described
above, the G-protein-coupled glutamate receptor mGluR1 is abundant in
Purkinje cell dendrites.10
mGluR1 is a postsynaptic,
G-protein-coupled receptor that activates phospholipase
C,16
thus playing a key role in the activation of PKC
by diacylglycerol (DAG) in Purkinje cells. An absence of mGluR1 in mice
results in motor impairment and disruption of cerebellar synaptic
plasticity.17,18
To assess the status of mGluR1 in B05/+ Purkinje cells, an
immunohistochemical analysis was performed. By this analysis, mGluR1
was readily detectable in Purkinje cell dendrites of 10-week-old B05/+
mice (Figure 7B)
, very similar to that
seen in 10-week-old wild-type Purkinje cells (Figure 7A)
. Although the
thickness of the molecular layer was considerably less in the B05/+
SCA1 cerebellum because of the atrophy of the Purkinje cell
dendrites at this age,4
mGluR1 was detectable throughout
the extent of B05/+ Purkinje cell dendrites. Thus, although the
vacuoles were immunoreactive for mGluR1, the immunohistochemical
analysis indicated that mGluR1 was not progressively lost from the
Purkinje cell dendrites as was seen with PKC. It is also worth
noting that the cytoplasmic Purkinje cell-specific protein, calbindin,
by immunofluorescence (Figure 5)
was retained in SCA1 mice
well beyond the age at which PKC became undetectable.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Second, we
found that the vacuoles were stained with a marker of the outer cell
membrane, wheat germ agglutinin, but not with markers specific to the
Golgi apparatus, endoplasmic reticulum, or lysosomes. These data
indicate that the vacuoles in the Purkinje cells of SCA1
transgenic mice originate from the plasma membrane.
These observations led to the conclusion that the formation of vacuoles
in the Purkinje cells of SCA1 transgenic mice involves the
internalization of the somatodendritic membrane. Moreover, these
observations led to the hypothesis that the formation of vacuoles is
the mechanism underlying the loss of dendritic membrane. In support of
this hypothesis are the findings that 1) the time course of vacuole
formation coincides with the loss of dendritic membranes; 2) the
dendritic proteins mGluR1, GluR1/2, GluR2/3, and PKC, were
detected in the cytoplasmic vacuoles; and 3) the vacuoles contained
proteins of the UPP suggesting that the vacuoles are involved with the
degradation of proteins. These points suggest that by a mechanism yet
to be determined, mutant ataxin-1 induces the bulk internalization of
Purkinje cell plasma membrane into vacuoles, which then recruit
components of the UPP. As the internalization of plasma membrane
proceeds, proteins associated with the dendrites are incorporated into
the vacuoles and degraded, leading to the dendritic atrophy
characteristic of SCA1 pathology.
The role of the UPP in the degradation of cytosolic and nuclear proteins is well established.19,20 The UPP also has an important role in the degradation of misfolded newly synthesized proteins that have been removed from the endoplasmic reticulum.21 In both of these instances the UPP system acts on nonmembrane-associated proteins. There are also a growing number of examples in which the ubiquitin/proteasome system is involved in the endocytosis of proteins from the plasma membrane.22-25 The present findings extend the role of the UPP to the degradation of proteins in vacuoles as part of the neurodegeneration induced by a disease-causing polyglutamine protein.
Several aspects of the membrane internalization are worth noting. In
SCA1 Purkinje cells, there is no evidence that specific
membrane proteins are selected for internalization as seen in
clathrin-dependent endocytosis. Rather, all of the membrane proteins
that were assessed were found in the cytoplasmic vacuoles, suggesting
that the membrane proteins are internalized by the bulk internalization
of the plasma membrane from the Purkinje cell soma (Figure 1)
.
Furthermore, clathrin-dependent endocytosis occurs at clathrin-coated
pits giving rise to small coated vesicles of less than 150 nm. The
large size of the vacuoles in the Purkinje cells of SCA1
transgenic mice is more typical of a clathrin-independent endocytosis
mechanism, such as macropinocytosis, that can lead to large endocytic
vesicles as large as 5.0 mm in diameter.27,28
These points
argue that the vacuoles found in the SCA1 transgenic
Purkinje cells are not formed by clathrin-mediated endocytosis, and may
be formed by a nonclathrin-mediated endocytosis mechanism.
By 13 weeks of age the levels of PKC were essentially undetectable
by Western blot and immunofluorescence. In contrast, at 13 weeks of age
mGluR1 and other components of the somatodendritic membrane were still
readily detectable by immunohistochemistry. This analysis indicates
that the loss of dendritic membrane proteins, eg, mGluR1, is protracted
and likely follows the loss of dendritic arborization that is not
complete until 27 weeks of age in the SCA1
mice.4
So why is PKC lost at a faster rate than the
dendritic membrane proteins? Perhaps the relative enhanced rate of
PKC degradation is correlated with its subcellular distribution in
SCA1 transgenic Purkinje cells. Early on, PKC membrane
association shifts from being primarily dendritic to being at the
plasma cell membrane (Figure 4)
. As discussed above, formation of the
cytoplasmic vacuoles seems to be the result of the bulk internalization
of membrane from the Purkinje cell soma. Thus, the redistribution of
membrane-associated PKC to the Purkinje cell plasma membrane would
enhance its uptake into the cytoplasmic vacuoles and potentiate its
degradation by the UPP. Consistent with this suggestion was the fact
that the vacuoles stained prominently for PKC (Figure 3F)
, much more
than for mGluR1 (Figure 2B)
, whose localization was maintained at the
dendritic membrane (Figure 7)
.
The changes in PKC subcellular distribution detected at 3 weeks
postnatally in the SCA1 mice are an early sign of an
alteration in Purkinje cell function induced by the expression of a
polyglutamine protein. In Purkinje cells of wild-type mice, a
substantial amount of the dendritic PKC localized to the inner
surface of the cell membrane. In the dendritic tree of transgenic
SCA1 Purkinje cells there was an almost complete loss of
PKC associated with the cell membrane. Because the translocation of
PKC to the membrane is a marker of its
activation,12-14
these data indicate that PKC normally
is more active in the dendrites of Purkinje cells than in the cell
body, and that an early event in the Purkinje cell disease of the
SCA1 mice is an alteration in the PKC dendritic-signaling
pathway. PKC isoforms are activated sequentially by calcium and
DAG.12,26
Repetitive calcium spikes result in PKC
translocation to the membrane where binding to DAG seems to function in
the retention of activated PKC at the plasma membrane. Thus, the
observed absence of membrane-associated PKC in the dendrites of
SCA1 transgenic Purkinje cells could be because of a
reduction in calcium spikes and/or reduction of DAG at the plasma
membrane. A potential source of external calcium are voltage-gated
calcium channels in the plasma membrane at the climbing fiber
synapse,27
and internally the inositol
triphosphate-mediated release of calcium in the endoplasmic
reticulum.28-30
Both IP3 and DAG would be produced as a
result of phospholipase C activation because of ligand interaction with
a G-coupled receptor,31
ie, parallel fiber release of
glutamate that acts on metabotropic G-coupled receptor mGluR1 on
Purkinje cells.32
It has been demonstrated that these
signals are followed by the activation of PKC, and that the activation
of PKC is required for the induction of cerebellar long-term
depression.33
It remains unclear the extent to which vacuole formation characterized in the SCA1 transgenic mice correlates with disease process in SCA1 patients. Purkinje cell cytoplasmic vacuoles have not been reported in SCA1 patient material.34 However, SCA1 patient pathological studies have been limited to autopsy material obtained at the end stage of disease, long after most Purkinje cells have disappeared. In aged SCA1 mice, when the Purkinje cell dendrites were essentially gone, the cytoplasmic vacuoles were no longer detected. Whether cytoplasmic vacuoles are a component of the disease in humans awaits examination of postmortem tissue form SCA1 patients at an early stage of disease, before the complete loss of the Purkinje cell dendritic tree.
Although the results reported here provide important insights into the molecular functions whose alteration is associated with the cytoplasmic pathology seen in Purkinje cells of SCA1 transgenic mice, they need to be placed in a broader picture of SCA1 pathogenesis in which the nucleus is clearly the site of the initial disease-causing events.6 Thus, the cytoplasmic alterations seen in the transgenic SCA1 Purkinje cells are likely triggered by mutant ataxin-1-induced events in the nucleus. The most likely scenario is that the cytoplasmic alterations are in response to changes in gene expression induced by mutant ataxin-1.7 The number and identity of those genes whose altered expression results in the altered trafficking of somatodendritic membrane proteins seen in SCA1 Purkinje cells remain to be determined.
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Acknowledgements |
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Footnotes |
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Supported by grant no. NS22920 from the National Institute of Neurological Disorders and Stroke/National Institutes of Health.
P. J. S. and C. A. V.-G. contributed equally to this work.
Accepted for publication May 14, 2001.
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H. Jiang, F. C. Nucifora Jr, C. A. Ross, and D. B. DeFranco Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein Hum. Mol. Genet., January 1, 2003; 12(1): 1 - 12. [Abstract] [Full Text] [PDF]
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T. Kobayashi, K. Tanaka, K. Inoue, and A. Kakizuka Functional ATPase Activity of p97/Valosin-containing Protein (VCP) Is Required for the Quality Control of Endoplasmic Reticulum in Neuronally Differentiated Mammalian PC12 Cells J. Biol. Chem., November 27, 2002; 277(49): 47358 - 47365. [Abstract] [Full Text] [PDF]
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