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Short Communications |
-, ß-, and 
-Synuclein Neuropathology
From the Department of Neurology,*
Medical College of
Pennsylvania Hahnemann University; the Department of Pathology
and Laboratory Medicine,
the
Center for Neurodegenerative Disease Research, and the
Department of Neurology,
the University of
Pennsylvania, Philadelphia, Pennsylvania
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-synuclein (S) in LB-like inclusions, glial
inclusions, and spheroids in the brains of three NBIA 1
patients. Further, ß-synuclein (ßS) and 
-synuclein
(S) immunoreactivity was detected in spheroids but not in LB-like or
glial inclusions. Western blot analysis demonstrated high-molecular
weight S aggregates in the high-salt-soluble and Triton
X-100-insoluble/sodium dodecyl sulfate-soluble fraction of the NBIA 1
brain. Significantly, the levels of S were markedly reduced
in the Triton X-100-soluble fractions compared to control
brain, and unlike other synucleinopathies, insoluble
S did not accumulate in the formic acid-soluble fraction. These
findings expand the concept of neurodegenerative synucleinopathies by
implicating S, ßS, and S in the pathogenesis of
NBIA 1.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pathologically, NBIA 1 is characterized by cerebral atrophy, symmetrical partially destructive lesions of the globus pallidus with iron deposition in the medial globus pallidus, red nucleus, substantia nigra pars reticularis, and dentate nucleus.1-4,10,11 The iron deposition results in a characteristic magnetic resonance image with a hypointense center surrounded by a hyperintense area in the pallidum ("eye of the tiger").8,12 The designation of NBIA 1 is increasingly used instead of the term Hallervorden-Spatz syndrome to describe this disorder.13 Associated with neuronal loss is an intense gliosis of the medial globus pallidus3,8,14 the external segment is typically spared.3 Muscle pathology includes myeloid structures, dense bodies, and fiber splitting.15 Nonnervous tissue may also be involved as liver and pituitary abnormalities have been described.16 Bone marrow biopsy has demonstrated sea-blue histiocytes and osmophilic inclusions8,17 have been described in lymphocytes suggesting that NBIA 1 is a systemic disorder.
The major histopathological hallmarks of NBIA 1 are axonal
spheroids,3,4,11,14
which have been shown to contain
immunoreactive (IR) neurofilament (NF) proteins,7,18,19
superoxide dismutase,11
amyloid precursor protein
(APP),20
and -synuclein (S).18,19,21
In
addition to spheroids, other characteristic lesions include glial
cytoplasmic inclusions (GCIs),18
Lewy body (LB)-like
intraneuronal inclusions (NCIs),7,13,18,19,22
and
dystrophic neurites (DNs),7,18,19
whereas in late onset
NBIA 1, tau pathology has been demonstrated14,22,23
consisting of both paired helical filaments and straight filaments
without amyloid ß-protein (Aß) deposition.
In this study, we examined three cases of NBIA 1 immunohistochemically
with antibodies to NFs, purified LBs, tau, Aß, APP, S, as well as
ß-synuclein (ßS) and -synuclein (S). Moreover, we also mapped
topographically-distinct epitopes extending throughout S in lesions
that were immunostained by anti-S antibodies, and we demonstrated
species of normal and abnormal S in the NBIA 1 brain by Western blot
analysis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Three autopsy proven cases (one infantile, one adult, one
late-onset) of NBIA 1 were obtained from the brain banks at the Center
for Neurodegenerative Disease Research, Case Western Reserve
University, and the Universities of Miami and Maryland (see Table 1
for clinical demographics). Tissue was
fixed in either 10% neutral buffered formalin or 70% ethanol/150
mmol/L NaCl and paraffin-embedded. The following brain regions were
examined: motor cortex, sensory cortex, midfrontal lobe, orbitofrontal
lobe, cingulate gyrus, superior temporal gyrus, amygdala, hippocampus
(anterior and posterior), visual cortex, insula, caudate, putamen,
globus pallidus, nucleus accumbens, basal forebrain, thalamus,
hypothalamus, midbrain/substantia nigra, pons/locus ceruleus, medulla,
cervical spinal cord, olfactory bulb, and trigeminal ganglion when
available. Serial sections of 6 µm thickness were analyzed.
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Histochemical studies were performed using hematoxylin and
eosin (H&E) and silver stains whereas immunohistochemistry was
performed using well-characterized antibodies as
described.24,25
The antibodies used here included those
specific for NF subunits (RMdO20, NFL),26
ubiquitin (mAb
1510, Chemicon, Temecula, CA),27
purified cortical LBs
(LB48),24
S (LB509, Syn204, Syn208,
SNL1),28,29
S/ßS (Syn202, Syn205, Syn214,
SNL4),29
ßS (Syn207),18
S
(antisera20),18
tau (17026),30
APP
(LN39),31
and Aß (2332).32
Sections
were probed by immunohistochemistry, developed using the
avidin-biotin-peroxidase complex method (Vector Labs,
Burlingame, CA) and then lightly counterstained with hematoxylin.
Sections were examined and graded semiquantitatively using the following system: 0 = no pathology, 1 = rare pathology, 2 = mild pathology, 3 = moderate pathology, and 4 = severe pathology. Each section was analyzed for synuclein IR spheroids, LBs, NCIs, GCIs, and DNs as well as for tau and amyloid pathologies.
Western Blot Analysis
Western blotting and biochemical fractionation were performed as described previously.29,33 Briefly, gray matter (0.3 gram) from the midfrontal cortex of NBIA 1 (Case Western Reserve) and a normal age-matched control brain was homogenized in 2 ml/gram of tissue of high-salt (HS) buffer (50 mmol/L Tris, pH 7.4, 750 mmol/L NaCl, 10 mmol/L NaF, 5 mmol/L ethylenediaminetetraacetic acid with protease inhibitors) and centrifuged at 100,000 x g for 30 minutes. The pellets were re-extracted and the supernatants were pooled. The pellets were sequentially extracted twice with 2 ml/gram of HS buffer/1% Triton X-100 (HS/T) and once with 1 ml/gram sodium dodecyl sulfate (SDS) sample buffer (1% SDS, 10% sucrose, 10 mmol/L Tris, pH 6.8, 1 mmol/L ethylenediaminetetraacetic acid, 40 mmol/L dithiothreitol). The pellets were extracted with 0.67 ml/gram 70% formic acid (FA) and disrupted with two sequential 2-second sonication bursts. FA was evaporated in an Automatic Environment SpeedVAc System (Savant Instruments, Holbrook, NY). SDS sample buffer (0.67 ml/gram) was added to the dried pellets, followed by vigorous vortex, and the pH was adjusted with NaOH. SDS sample buffer was added to the HS and HS/Triton fraction and all of the samples were boiled for 5 minutes. The FA samples were centrifuged at 13,000 x g for 5 minutes to remove insoluble debris. Five µl of each fraction was loaded in separate lanes for SDS-polyacrylamide gel electrophoresis followed by Western blot analysis.29,33
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Two of the three brains exhibited severe atrophy with mildly
dilated ventricles. The third brain (late onset) had marked ventricular
dilatation without significant atrophy (see Table 1
). All of the cases
examined had iron accumulation in the globus pallidus, substantia
nigra, red nucleus, and dentate nucleus whereas microscopic evaluation
revealed neuronal loss with gliosis. The infantile onset case also
displayed marked loss of anterior horn cells in cervical and lumbar
spinal cord. Dystrophic axon spheroids were noted with H&E and silver
stains in the basal ganglia and brainstem in all three cases.
Synuclein Pathology
S pathology was seen throughout all three NBIA 1 brains (Figure 1)
. For example, S IR NCIs and
spheroids were abundant in the globus pallidus, putamen, thalamus,
midfrontal gyrus, precentral gyrus, postcentral gyrus, amygdala, and
entorhinal cortex (Figure 1, A–H)
. In addition, most cortical regions
displayed numerous S-positive DNs, but they were most prominent in
the CA2/3 region of the hippocampus (Figure 1I)
. Antibodies specific
for ßS and S labeled axonal spheroids but not NCIs or
DNs.
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illustrate representative ßS IR spheroids
in the cingulate gyrus, inferior olive, cervical spinal cord, and
putamen, respectively, whereas panels N to O in Figure 1
show typical
S IR spheroids in the cingulate and midfrontal cortices. However,
similar NCI, DNs and spheroids also were detected with antibodies to NF
proteins and ubiquitin (data not shown) as well as with antibodies
raised against purified cortical LBs (LB48) that recognize the
mid-sized NF subunit24
as shown in Figure 1, P–Q
.
Finally, GCIs in white matter oligodendrocytes were best demonstrated
with antibodies specific for S (Figure 1R)
but not by antibodies to
ßS or S (data not shown). Tau and Aß Pathology
Senile plaques were not detected in any of the three cases by
immunohistochemistry with antibodies to Aß or by
silver-staining methods. However, many dystrophic processes were
labeled by antibodies to Aß (Figure 1S)
and to APP (data not shown).
Dystrophic neurites also were labeled with antibodies to tau proteins
(Figure 1T)
. Rare neurofibrillary tangles were noted in the entorhinal
cortex of the late onset case whereas the brain of the Center for
Neurodegenerative Disease Research case contained tau IR glial tangles
in the hippocampus and entorhinal cortex (Figure 1, U–V)
.
Epitope Analysis
To define the extent to which S was incorporated in
neuropathological lesions in the NBIA 1 brain, we used antibodies
specific for defined epitopes in different domains spanning the S
molecule in immunohistochemical epitope mapping studies (Figure 2)
. Remarkably, we noted variations in
staining intensity and pattern of distinct lesions with different
epitope-specific anti-S antibodies. For example, NCIs, DNs, and
spheroids were seen best with LB509, which recognizes amino acids 115
to 122 in S28
and the S amino-terminal antibody SNL4
(amino acids 2 to 12).29
In contrast, NCIs, DNs, and
spheroids were less immunoreactive with antibodies directed against the
carboxy-terminal region of S (ie, Syn202, Syn205, and Syn214 to
epitopes within amino acids 130 to 140).29
The antibodies
directed against the hydrophobic-middle region of S, (ie, Syn204 and
Syn208 to epitopes in amino acids 87 to 110 and SNL1 to amino acids 104
to 119)29
poorly stained NCIs and DNs. Almost no spheroids
were detectable with Syn208 and none were labled with Syn204 or SNL1.
Moreover, LB509, SNL4 and the carboxy-terminal antibodies (Syn202,
Syn205, and Syn214) stained NCIs in a dense homogenous pattern
whereas the antibodies to the middle hydrophobic region of S
(Syn204, Syn208, and SNL1) displayed a less intense puntate pattern of
immunoreactivity. Finally, GCIs were seen best by LB509 and SNL4 but
they were difficult to recognize with the other antibodies against S
(data not shown).
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Western blot analysis demonstrated the presence of S in the
HS-soluble fraction in the control and NBIA 1 brains (Figure 3
, lanes 1–2), however there was a
marked increase in high-molecular weight aggregates in the NBIA 1. In
contrast to the control brain (Figure 3
, lane 3), however, there was a
significant reduction in the levels of S in the HS/T-soluble
fraction of the NBIA 1 brain (Figure 3
, lane 4, small arrow). In the
SDS-soluble fraction from the NBIA 1 brain, there was an accumulation
of high-molecular weight aggregates of S (Figure 3
, lane 6, large
arrow), but not in the control case (Figure 3
, lane 5). In comparison
to other synucleinopathies, ie, Parkinson’s disease (PD), dementia
with LBs (DLB), and multiple system atrophy, S did not
aggregate or accumulate in the FA-soluble fraction of the control or
NBIA 1 brains (Figure 3
, lanes 7 and 8, respectively).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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S gene have been described in rare
familial PD kindreds.34,35
LBs of sporadic and familial
PD, DLB, the LB variant of Alzheimer’s disease (AD),36,37
familial AD,33
and Down’s syndrome38
are
also composed primarily of S, but other proteins, such as NF
subunits, are found consistently in these inclusions.24,37
In addition, S is a major component of GCIs in multiple system
atrophy.18,39
NBIA 1 is a rare neurodegenerative disorder
with neuronal, axonal, and glial pathology that may be widely
distributed or relatively restricted in the central nervous system.
Whereas many cases begin in the late juvenile to early adult years,
there have been reports of late onset cases,4,14
including
one of the cases described here. The histopathological hallmark of NBIA
1 is the axonal spheroid that seems to be primarily comprised of
insoluble S.
In addition to S-rich spheroids, we show here that S IR NCIs,
GCIs, and DNs are dispersed throughout the NBIA 1 brain. These
pathological lesions, together with iron deposition, distinguish NBIA 1
from other synucleinopathies. Significantly, AD pathology may be absent
from NBIA 1 brains even when patients with this disorder become
demented. Although our cases showed no evidence of Aß IR plaques and
tau IR neurofibrillary tangles were very rare in the late onset case,
the Center for Neurodegenerative Disease Research brain had abundant
tau IR glial tangles that also were weakly immunostained by antibodies
to S.
Recently, it was reported that NCIs but not spheroids in NBIA 1 brains
are S IR.19
The discordance between the results in this
study and the data described here may be because of a number of factors
including differences in the specificities of the anti-S antibodies
used in each study. Indeed, our epitope mapping study, using antibodies
to topographically separate antigenic sites throughout S, suggests
that SNL4 (amino terminal, amino acids 2 to 12) and LB509 (amino acids
115 to 122) are the most sensitive probes for detecting axon spheroids.
Moreover, consistent with a previous report,22
we show
here carboxy-terminal-specific antibodies (Syn202, Syn205, Syn214) as
well as antibodies to epitopes in the hydrophobic central region of
S (Syn204, Syn208, and SNL1) label these spheroids weakly or not at
all, and are less sensitive for detecting NCIs and DNs. Notably, LB509,
which recognizes an epitope between the hydrophobic-middle and the
carboxy-terminal regions of S, labels S IR pathology in the NBIA
1 brains more intensely than antibodies to the two flanking regions.
Thus, the LB509 epitope may be more accessible for antibody binding
than the flanking epitopes detected by our other anti-S antibodies,
and this may reflect pathological alterations of S specific to NBIA
1. Nonetheless, our study confirms and extends previous reports that
axonal spheroids in the NBIA 1 brain are robustly labeled by antibodies
to S.18,21
Although initially, ßS and S had not been implicated in
neurodegenerative disease,25
we reported recently that the
hippocampus of patients with PD and DLB contain pathological aggregates
of S and ßS in mossy fiber projections as well as S IR
spheroids in the molecular layer of the dentate gyrus.25
S IR spheroids were not seen in other disorders with axonal
dilatations such as Pick’s disease.25
Here, we extend
these findings by demonstrating ßS and S IR spheroids in another
neurodegenerative disease, ie, NBIA 1. However, the ßS IR vesicular
pathology that we detected in PD and DLB25
was not seen in
NBIA 1.
Significantly, our Western blot analysis demonstrated S in the
HS-soluble fraction of both the control and NBIA 1 brains, but multiple
higher molecular weight species of S were more prominent in this
fraction of the NBIA 1 brain. Moreover, there also was a dramatic
reduction of S in the HS/T fraction of the NBIA 1 brain compared to
control, similar to that reported in familial AD.33
Because this fraction may represent a membrane-bound S component,
the loss of membrane integrity, perhaps including synaptic vesicle
membranes may be a common feature of several different
synucleinopathies. A significant pool of high-molecular weight species
of S accumulated in the SDS-soluble fraction only in the NBIA 1
brain, some of which failed to enter the gel. Interestingly, little or
no S was detected in the FA fraction. Although this distinguishes
NBIA 1 from other synucleinopathies, ie, multiple system atrophy and
familial AD with LBs,33
where S has been
detected in the FA fraction, the reasons for this remain to be
elucidated.
The aggregation of normally soluble proteins into fibrillar lesions is
the neuropathological hallmark of many diseases. The involvement of
S, ßS, and S in the neuronal, glial, and axonal pathology in
NBIA 1 continues to expand the concept of neurodegenerative
synucleiopathies.37,39-42
Although it is not known if the
conversion of soluble normal proteins into insoluble variants that form
pathological aggregates (ie, LBs, GCIs, and spheroids) causes
neurodegeneration, it is likely that these alterations impair the
long-term viability of neurons. For example, we have previously
proposed24,25,37,41
that LB-containing neurons could
undergo a dying-back phenomenon caused by LBs that block axonal
transport, thereby disconnecting one brain region from another.
Similarly, S-rich axonal spheroids of NBIA 1 could interfere with
the transport of important structural or functional proteins to distal
intracellular targets. Continued efforts to elucidate the pathological
mechanisms leading to the conversion of soluble proteins, such as S,
into insoluble aggregates as NCIs, as well as the accumulation of
proteins such as S, ßS, and S in axonal spheroids could lead to
novel diagnostic and therapeutic strategies to treat the large number
of patients with clinically diverse synucleinopathies such as PD, DLB,
and multiple system atrophy as well as the rare patients with NBIA 1.
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Acknowledgements |
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Footnotes |
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Supported by grants from the National Institute on Aging and a Pioneer Award from the Alzheimer’s Association. B. G. is a recipient of a fellowship from the Human Frontier Science Program Organization.
J. E. G. and B. G. contributed equally to this manuscript
Accepted for publication May 4, 2000.
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References |
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-synuclein in multiple system atrophy. Am J Pathol 1999, 155:1241-1251This article has been cited by other articles:
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