REVIEW
Involvement of the peripheral nervous systemin synucleinopathies, tauopathies and otherneurodegenerative proteinopathies of the brain
Koichi Wakabayashi • Fumiaki Mori •
Kunikazu Tanji • Satoshi Orimo • Hitoshi Takahashi
Received: 25 March 2010 / Revised: 29 May 2010 / Accepted: 29 May 2010 / Published online: 9 June 2010
� Springer-Verlag 2010
Abstract Involvement of the peripheral nervous system
(PNS) is relatively common in some neurodegenerative
proteinopathies of the brain and may be pathogenetically
and diagnostically important. In Parkinson’s disease, neu-
ronal a-synuclein aggregates are distributed throughout the
nervous system, including the central nervous system
(CNS), sympathetic ganglia, enteric nervous system, car-
diac and pelvic plexuses, submandibular gland, adrenal
medulla and skin. The pathological process may target the
PNS and CNS at the same time. In multiple system atro-
phy, numerous glial cytoplasmic inclusions composed of
filamentous a-synuclein are widely distributed in the CNS,
while a-synuclein accumulation is minimal in the sympa-
thetic ganglia and is restricted to neurons. Neurofibrillary
tangles can occur in the sympathetic and spinal ganglia in
tauopathy, although they appear to develop independently
of cerebral Alzheimer’s disease pathology. In amyotrophic
lateral sclerosis, neuronal loss with TDP-43-positive neu-
ronal cytoplasmic inclusions in the spinal ganglia is more
frequent than previously thought. Peripheral ganglia and
visceral organs are also involved in polyglutamine dis-
eases. Further elucidation and characterization of PNS
lesions will have implications for intravital biopsy
diagnosis in neurodegenerative proteinopathy, particularly
in Parkinson’s disease.
Keywords a-Synuclein � Enteric nervous system �Lewy body � Parkinson’s disease � Tauopathy � TDP-43
Introduction
Common cellular and molecular mechanisms including
protein aggregation and inclusion body formation are
involved in many neurodegenerative diseases [82, 135].
a-Synuclein is a major component of Lewy bodies (LBs) in
Parkinson’s disease (PD) and dementia with LBs (DLB)
[176] as well as in neuronal and glial cytoplasmic inclu-
sions (GCIs) in multiple system atrophy (MSA) [170]. Tau
is a principal component of neurofibrillary and glial tangles
in tauopathies [77]. Expanded polyglutamine repeats are
found in intranuclear and cytoplasmic inclusions in
hereditary neurodegeneration, including Huntington’s
disease [178]. Recently, TDP-43 was identified as a com-
ponent of ubiquitinated inclusions in amyotrophic lateral
sclerosis (ALS) and frontotemporal lobar degeneration
[8, 106].
PD is traditionally considered as a movement disorder
with hallmark lesions in the brainstem pigmented nuclei
(substantia nigra and locus ceruleus). However, accumu-
lating evidence suggests that non-motor complications
(cognitive, psychiatric, autonomic, sleep and sensory
disorders) are also common in PD [86, 91]. Pathological
changes occur in widespread regions of the central and
peripheral nervous systems (PNS) in this disease [21, 40,
41]. Furthermore, primary glial involvement (‘‘gliodegen-
eration’’) can be observed in a-synucleinopathy [29, 177]
as well as in tauopathy [31, 58].
K. Wakabayashi (&) � F. Mori � K. Tanji
Department of Neuropathology, Institute of Brain Science,
Hirosaki University Graduate School of Medicine,
5 Zaifu-cho, Hirosaki 036-8562, Japan
e-mail: [email protected]
S. Orimo
Department of Neurology, Kanto Central Hospital,
Tokyo, Japan
H. Takahashi
Department of Pathology, Brain Research Institute,
University of Niigata, Niigata, Japan
123
Acta Neuropathol (2010) 120:1–12
DOI 10.1007/s00401-010-0706-x
Inclusion bodies are considered to be related to neuronal
degeneration, which does not imply that the inclusions are
always fatal to the neurons [10, 158]. Recent studies have
suggested that oligomers and protofibrils are cytotoxic, and
that inclusions may represent a cytoprotective mechanism
in neurodegenerative proteinopathy [43, 135, 160]. How-
ever, the number of LBs in patients with mild to moderate
loss of neurons in the substantia nigra is higher than in
those with severe neuronal depletion, thereby suggesting
that LB-containing neurons may be dying neurons [176].
The present article reviews neuropathological data
concerning the PNS involvement in neurodegenerative
disorders of the brain. Particular focus is given to abnormal
protein accumulation and inclusion body formation outside
the central nervous system (CNS).
Parkinson’s disease and dementia with Lewy bodies
The histological hallmark of PD and DLB is neuronal
a-synuclein aggregates called LBs and Lewy neurites. To
date, more than 70 molecules have been identified in LBs
[176], in which phosphorylated a-synuclein is a major
constituent [49]. It is now known that the substantia nigra is
not the only or the first brain region involved in PD [34].
Braak et al. [22] proposed a pathological staging scheme
for PD, in which early a-synuclein pathology is present in
the dorsal vagal nucleus and in the olfactory bulb. This
staging system characterizes a progression from the dorsal
vagal nucleus (stage 1), through the pontine tegmentum
(stage 2), into the midbrain and neostriatum (stage 3), and
then the basal prosencephalon and mesocortex (stage 4),
and finally through the neocortex (stages 5 and 6) [17, 22,
102]. Braak PD stages 1–3 correspond to incidental LB
disease, which is considered to represent presymptomatic
PD and/or DLB [1, 11, 35, 39, 134]. Saito et al. [136] also
proposed a pathological staging scheme for the progression
of LB disease (PD and DLB). Accumulation of a-synuclein
is also found both in astrocytes and oligodendrocytes in the
brain of patients with PD and DLB [25, 166].
LBs are widely distributed in the brain of patients with
PD [114] and DLB [80] mentioned above. a-Synuclein
abnormality is found in 10% of pigmented neurons in the
substantia nigra and more than 50% of those in the locus
ceruleus [101]. LBs are also found in the spinal cord,
including the intermediolateral nucleus, dorsal horn and
sacral autonomic nucleus [12, 14, 24, 76, 115, 125, 168].
Except for olfactory structures and spinal dorsal horn,
sensory components of the nervous system are relatively
spared. LBs are also found in the PNS even in the early
stage of PD (described below). The widespread distribution
of Lewy pathology may correspond to a variety of motor
and non-motor symptoms of PD [40, 91].
Sympathetic ganglia
LBs in the sympathetic ganglia were first observed by
Herzog [57]. In the ganglia, LBs occur mainly in the nerve
cell processes (Fig. 1a, b), and the majority of LB-con-
taining processes are unmyelinated axons [45, 171].
Although paravertebral and celiac sympathetic ganglia are
the predilection sites for LBs [37, 169], no LBs are found
in the dorsal root ganglia.
The degenerative process of the sympathetic ganglia has
been classified into three categories [117]. In the early
stage, a few LBs are observed in the ganglia but the
number of neurons and immunoreactivity for tyrosine
hydroxylase (TH), a rate-limiting enzyme of the catechol-
amine synthesizing pathway, is well preserved. In the
middle stage, many LBs are found in the ganglia but the
number of neurons appears to be normal on H&E stained
sections. Interestingly, a significant number of neuronal
somata (about 20–30% of neurons) is TH-immunonegative.
In the advanced stage, there is apparent neuronal loss in the
ganglia on H&E stained or TH immunostained sections.
The number of LBs is decreased compared with the middle
stage [117].
Parasympathetic nervous system
The largest source of preganglionic parasympathetic fibers
is the dorsal vagal nucleus, which supplies all the thoracic
and abdominal viscera except those in the pelvic region
[128]. In the cranial region, the postganglionic fibers derive
from ciliary, pterygopalatine, submandibular and otic
ganglia [128]. The occurrence of LBs has been reported in
the ciliary [7] and submandibular ganglia [153]. Recently,
Del Tredici et al. [33] have shown that Lewy pathology
occurs in the submandibular glands and in anatomically
related structures (superior cervical ganglia, cervical sym-
pathetic trunk and peripheral vagal nerve) in PD (9/9 cases)
and incidental LB disease (2/3 cases) but not in MSA or
controls. The presence of Lewy pathology in the autonomic
nerves and/or ganglia innervating the submandibular
glands might be related to the reduced salivary secretion
that accompanies PD [33].
Enteric nervous system
Gastrointestinal dysfunction is a common feature of PD
[1, 27, 97, 129], and constipation is frequent in DLB [59].
The occurrence of LBs in the enteric nervous system (ENS)
of PD patients was first reported by Qualman et al. [133]
who recognized the inclusions in the myenteric plexus of
the esophagus of 1 patient and the colon of another out of
22 patients with PD. They also found similar inclusions in
the esophagus in two out of eight patients with esophageal
2 Acta Neuropathol (2010) 120:1–12
123
achalasia. Kupsky et al. [85] reported the occurrence of
LBs in the myenteric and submucosal plexuses of the
surgically resected colon and biopsied rectum of a patient
with PD and megacolon. Wakabayashi et al. [175] dem-
onstrated that LBs were distributed widely in the myenteric
and submucosal plexuses from the upper esophagus to the
Fig. 1 Lewy pathology in the peripheral nervous system in Parkin-
son’s disease. a Intracytoplasmic (arrows) and intraneuritic Lewy
bodies (arrowheads) in the sympathetic ganglia. b a-Synuclein-
immunoreactive neuritic structures in the sympathetic ganglia.
c Lewy body in the submucosal plexus of the rectum (arrowhead).
d Lewy bodies in the myenteric plexus of the lower esophagus.
e, f Lewy bodies in the cardiac sympathetic nerves. g Lewy bodies in
the adrenal medulla (arrowheads). h a-Synuclein-immunoreactive
neuritic structures in the subcutaneous tissue (arrowheads). a, c, ghematoxylin–eosin, b, d, f, h a-synuclein immunostain, e tyrosine
hydroxylase immunostain. Bars 20 lm
Acta Neuropathol (2010) 120:1–12 3
123
rectum and were most frequent and numerous in the
myenteric plexus of the lower esophagus (Fig. 1c, d).
Recently, Beach et al. [12] have shown that there is a
rostrocaudal gradient of decreasing frequency and density
of phosphorylated a-synuclein histopathology in the gas-
trointestinal tract in LB disorders. The submandibular
gland and lower esophagus have the greatest involvement
and the colon and rectum the lowest.
A similarity has been noticed between the distribution of
LBs and that of monoaminergic neurons in the CNS [114].
In addition, intrinsic neurons immunoreactive for TH exist
in the human ENS [172]. Interestingly, these neurons are
most frequent and numerous in the myenteric plexus of the
lower esophagus, which is the site where most LBs occur in
PD [12, 175]. However, LB-containing TH-immunoreac-
tive neurons have been rarely encountered in PD. In the
gastrointestinal tract, most LBs were found in the vasoac-
tive intestinal polypeptide (VIP)-immunoreactive processes
[173]. The majority of VIP-immunoreactive processes in
the ENS are intrinsic in origin. In addition, VIP is a cho-
linergic co-transmitter in the intrinsic innervation of the
human gastrointestinal tract [6]. However, there was no
significant decrease in the number of cholinergic or VIP
neurons in PD [145] as well as in MPTP-treated mice and
monkeys [5, 28]. The number of TH-immunoreactive
neurons has been reported to be relatively preserved in PD
patients [145] and decreased in MPTP monkeys [28]. In
contrast, the number of dopaminergic neurons in the
colonic myenteric plexus was markedly reduced in patients
with advanced PD [145]. Loss of dopaminergic neurons
was also found in MPTP mice [5]. The discrepancy
between the frequency of LBs and the severity of VIP
neuron loss may imply that Lewy neurites cause dysfunc-
tional axonal transport but do not cause neuronal cell death.
In the CNS, early sites of Lewy pathology are the
olfactory bulb and dorsal vagal nucleus [22, 34, 141].
Several investigators proposed that a neurotropic pathogen
enters the brain via two routes (1) anterogradely, via
olfactory pathway; and (2) retrogradely, via gastric nerve
plexus and preganglionic nerve fibers of the dorsal vagal
nucleus [20, 23, 55, 88]. Abbott et al. [1] have shown that
constipation could be one of the earliest markers of the
beginning of PD processes. This is supported by the find-
ings that LBs can occur in the ENS in elderly individuals
without LBs in the CNS [175] and that a-synuclein
accumulation has been seen in the gastric plexus in Braak
PD stage 2 [20]. Interestingly, a-synuclein aggregates in
the ENS precede the CNS and cardiac autonomic abnor-
malities in transgenic mice containing PD-associated
a-synuclein gene mutations [84]. It is possible that the
pathological process of PD targets the ENS even before
lower brainstem nuclei become involved. Lebouvier et al.
[87] performed routine colonic biopsies in five PD patients
complaining of constipation and five age-matched control
patients, and immunohistochemical staining revealed
phosphorylated a-synuclein-immunoreactive neurites in
the submucosal plexus in four out of five PD patients.
Colonic biopsies may be useful to detect LB-type degen-
eration in PD.
Recently, several studies have shown that PD patients
who had long-term survival of transplanted fetal nigral
tissue (11–16 years) developed LBs in grafted neurons [79,
89]. This suggests that Lewy pathology could be induced in
cells by prion-like transmissible agents [2, 23, 116]. The
mucosa of foregut receives the efferent fibers from the
dorsal vagal nucleus. Moreover, a link between Helico-
bacter pylori infection and PD has been suggested [3, 42].
If the postulated pathogen could penetrate the gastric
mucosa, it ascends retrogradely in preganglionic para-
sympathetic fibers of the vagus nerve to the medulla
oblongata [20]. This possibility deserves further
investigation.
Heart
The sympathetic neurons in the cervical and upper thoracic
ganglia are the origin of the postganglionic fibers inner-
vating the heart, namely, the cardiac sympathetic nerves.
The heart also receives parasympathetic cholinergic fibers
from the dorsal vagal nucleus. The density of sympathetic
nerves is six times higher than that of cholinergic fibers in
the anterior wall of the left ventricle [73]. In PD, LBs are
found in the ganglia located in the interatrial groove (atrial
ganglia) and in the nerve fibers around the coronary arteries
and in the myocardium (Fig. 1e, f) [169]. LBs are also
found in the heart of patients with incidental LB disease
[62].
Reduced cardiac uptake of meta-iodobenzylguanidine
(MIBG), a physiological analog of noradrenaline, on [123I]
MIBG myocardial scintigraphy has been reported in
patients with LB disorders [118]. Decreased cardiac uptake
of MIBG in LB disease reflects loss of cardiac sympathetic
nerves in the ventricular wall [4], which precedes the neu-
ronal loss in the sympathetic ganglia [117]. The depletion
of sympathetic nerves involves not only the ventricles, but
also the atria and the conduction system [51]. Accumula-
tion of a-synuclein in the distal axons of the cardiac
sympathetic nervous system precedes that in neuronal
somata or neurites in the paravertebral sympathetic ganglia
and heralds centripetal degeneration of the cardiac sym-
pathetic nerves in PD [123]. Cardiac sympathetic
denervation begins in the early disease process of PD [51,
122]. Cardiac sympathetic denervation and a-synuclein
pathology increase with disease duration and severity [48].
Similar degeneration occurs in PARK4 (familial PD linked
to SNCA duplication) [51, 124], but not in PARK2 (familial
4 Acta Neuropathol (2010) 120:1–12
123
PD linked to parkin mutations without LBs) [119].
Reduced cardiac uptake of MIBG is a potential biomarker
for the presence of LBs [118]. Interestingly, reduced car-
diac uptake of MIBG is also reported in idiopathic REM
sleep behavior disorder [99]. However, it is uncertain
whether idiopathic REM sleep behavior disorder is a forme
fruste of LB disease or not.
Recently, Miki et al. [95] reported the presence of LBs
and Lewy neurites solely in the cardiac sympathetic nerves
and stellate ganglia of a non-parkinsonian young adult at
autopsy. This singular finding is not consistent with the
‘‘dual-hit’’ hypothesis mentioned above [55].
Pelvic organs
In the pelvic plexus, LBs are found in the ganglia near the
urinary bladder and accessory male genital organs [169] as
well as in the ovary [12]. Wakabayashi et al. [169] have
reported that LBs were found in the pelvic plexus in 11 out
of 30 patients with PD. Minguez-Castellanos et al. [98]
examined surgical specimens from 100 patients without
known neurodegenerative disorders, who ranged in age
from 44 to 84 years and reported that a-synuclein aggre-
gates were found in the abdominopelvic autonomic
plexuses in 9% of the whole sample but were more com-
mon in vesicoprostatic (26.1%) than in digestive tract
specimens (3.9%). Although the most widely accepted
mechanisms of urinary and sexual dysfunctions in PD are
thought to be related to nerve cell loss in the CNS [13, 94],
Lewy pathology in the pelvic plexus may also play a role in
these conditions.
Adrenal gland
LBs occur in the nerve plexuses around the adrenal gland
and in the ganglion cells in the adrenal medulla (Fig. 1g)
[169, 174]. These ganglion cells are observed singly or in
small groups and are sympathetic in nature. Fumimura et al.
[50] reported that the accumulation of a-synuclein was
found in the adrenal gland in 207 (26.4%) of 783 cases
ranging in age from 48 to 104 years, with 1 case solely in the
adrenal gland. LBs in the adrenal medulla are easily dif-
ferentiated from adrenal bodies [36] observed in the
noradrenaline-containing chromaffin cells because the latter
are positive for periodic acid-Schiff but immunonegative for
ubiquitin and a-synuclein [149]. Interestingly, the number
of adrenal bodies in LB disease is significantly higher than
that in controls, and correlated with disease duration [149].
Other visceral organs
Recently, Beach et al. [12] have shown that Lewy pathol-
ogy occurs in multiple visceral organs including the
respiratory tract (larynx and bronchus), endocrine system
(pancreas and parathyroid gland) and genitourinary tract in
Lewy body disorders.
Skin
Ikemura et al. [61] prospectively examined skin samples
from the abdominal wall and upper limb in 279 consecu-
tively autopsied patients ranging in age from 52 to
104 years (mean 80.8 years) and showed that a-synuclein
immunoreactivity was present in the dermis in 20 (23.5%)
of 85 patients with Lewy pathology in the CNS. The latter
authors also retrospectively examined the abdominal skin
in 142 patients with Lewy pathology in the CNS and
demonstrated that the sensitivity of Lewy pathology in the
skin was 70% in PD and 40% in DLB. Dabby et al. [30]
performed 4-mm punch biopsies from the lower limb in 22
patients with PD and 19 controls using anti-PGP 9.5 anti-
body as a panneuronal marker. They reported that
cutaneous autonomic innervation was decreased in PD
compared to controls and that the denervation scores were
significantly correlated with disease duration in PD.
Nolano et al. [113] also performed 3-mm punch skin
biopsies from the fingertip, thigh and distal leg in 18
patients with PD and 30 controls and demonstrated
significant loss of epidermal nerve fibers in PD patients.
Recently, Miki et al. [96] immunohistochemically exam-
ined cutaneous tissue obtained from 6-mm punch biopsies
in 20 clinically diagnosed PD patients using phosphory-
lated a-synuclein immunohistochemistry. Abnormal
a-synuclein accumulation was found in the dermis of the
thoracic wall but not in the lower limb in 2 (10%) of 20
patients with PD (Fig. 1h). This suggests that skin biopsy
may not be suitable for the diagnosis of PD.
Pure autonomic failure and Lewy body dysphagia
From clinical and neuropathological viewpoints, primary
autonomic failure is divided into three types: pure auto-
nomic failure (PAF) without other neurological conditions,
autonomic failure with PD and autonomic failure with
MSA. In PAF, the main pathological findings are neuronal
loss in the intermediolateral column of the spinal cord and
sympathetic ganglia and the occurrence of LBs in the
brainstem pigmented nuclei, sympathetic ganglia, myen-
teric plexus, epicardium, adrenal medulla and urinary
bladder [7, 52, 71, 162]. Pigmented neurons in the sub-
stantia nigra and locus ceruleus are well preserved in PAF.
Cardiac sympathetic denervation has been observed in PAF
[121]. Skin biopsy revealed a-synuclein accumulation in
the skin nerve fibers in a patient with PAF [144]. Kauf-
mann et al. [72] reported two cases present with PAF; one
Acta Neuropathol (2010) 120:1–12 5
123
developed PD 20 years after onset of the disease and the
other developed DLB 4 years later. Similar cases have
been reported by several investigators [67, 182]. PAF is an
extreme variant of LB disorders, in which LB-type
degeneration may begin outside the CNS. Given the dis-
tribution and severity of Lewy pathology, PAF and a
significant proportion of PD may represent a ‘‘bottom-up’’
variant of LB disease, whereas cerebral type LB disease
[81] represents a ‘‘top-down’’ variant of LB disease.
The presence of LBs in autonomic structures could
explain isolated progressive dysphagia without extrapyra-
midal symptoms, i.e., LB dysphagia [66, 83]. Postmortem
examination has shown that neuronal loss with LBs was
chiefly restricted to the dorsal vagal nucleus in patients
with LB dysphagia [66, 83].
It is important to note that PAF and LB dysphagia are not
incompatible with early stages (or an early phase) of PD.
Multiple system atrophy
Multiple system atrophy is a sporadic adult-onset neuro-
degenerative disease, which is characterized by
striatonigral degeneration, olivopontocerebellar atrophy
and preganglionic autonomic lesions in any combination.
The histological hallmark is the presence of GCIs [105,
127] that contain many substances, including ubiquitin,
a-synuclein and p25a [170, 177]. The incidence of GCIs is
correlated with the severity of neuronal loss in the olivo-
pontocerebellar system as well as in the striatonigral
system [126]. Fibrillary inclusions are also found in the
neuronal somata, axons and nucleus [9, 107, 108, 164].
Severe atrophy of the frontal or temporal lobes has also
been reported in some cases of MSA [78, 131, 143]. The
primary motor cortex and spinal anterior horn are also
involved in MSA [148, 155, 161]. Thus, the neuropathol-
ogy of MSA is more extensive than previously thought.
The PNS is also affected in MSA. Filamentous aggre-
gates of a-synuclein are found in neurons in the
sympathetic ganglia [107]. Sone et al. [146] reported that
a-synuclein-immunoreactive neuronal inclusions were
found in the sympathetic ganglia in 11 out of 26 cases with
MSA and that the mean disease duration in cases with
a-synuclein inclusions was significantly longer than those
without. Although a-synuclein immunoreactivity is present
in the cytoplasm of Schwann cells [100], abnormal accu-
mulation of a-synuclein has not been reported in the PNS
glial cells. Sural nerve biopsy from patients with MSA
shows a reduction of unmyelinated fibers (sensory afferent
fibers and postganglionic sympathetic fibers) by 23% [68].
Mild degeneration of cardiac sympathetic nerves can occur
in MSA [120]. Thus, no portion of the nervous system
appears to be spared in MSA.
Tauopathy
Tauopathies comprise a group of neurodegenerative dis-
orders that share accumulation of phosphorylated tau in
selected vulnerable neurons and glial cells in the brain,
including Alzheimer’s disease (AD) [16, 19, 60, 104],
progressive supranuclear palsy (PSP) [64, 147], cortico-
basal degeneration (CBD) [38, 54], argyrophilic grain
disease [18, 44, 138] and Pick disease [77]. The spinal cord
is also involved in the disease process of AD [137], PSP
[63, 70, 75], CBD [65] and Guam parkinsonism-dementia
complex [93].
The occurrence of neurofibrillary tangles (NFTs) in the
PNS was first reported in the upper cervical ganglia in a
76-year-old man by Kawasaki et al. [74], who also dem-
onstrated that the NFTs are ultrastructurally composed of
paired helical filaments. To date, 10 autopsy cases with
NFTs in the paravertebral and prevertebral (celiac) sym-
pathetic ganglia have been reported [15, 74, 154, 163, 165].
All of these patients were over the age of 60 (age range
61–96 years; mean 78.8 years) and concomitant AD
lesions (many NFTs and senile plaques in the brain) were
found in only three cases. In addition, no NFTs were found
in the sympathetic ganglia of 27 patients with AD [140]
and in 20 patients with AD [165]. Shankle et al. [142]
examined the myenteric plexuses of 18 patients with AD
using an anti-tau antibody (Alz-50) and found no NFTs in
the plexuses. These findings suggest that NFTs in the
sympathetic ganglia develop independently of AD.
Nishimura et al. [112] reported that NFTs were found in
the spinal ganglia in two out of five patients with PSP. The
two patients’ ages were 76 and 71 years at death. Although
NFTs present in the CNS in PSP patients are ultrastructur-
ally composed of 15-nm-wide straight tubules [152, 157],
the NFTs observed in the spinal ganglia were composed of
paired helical filaments. However, immunohistochemical
study using antibodies against phosphorylation-dependent
and -independent tau has shown that no NFTs were detected
in the spinal ganglia of 8 patients with PSP and of 20
patients with AD [165]. The occurrence of NFTs in the
spinal ganglia may be unrelated to the occurrence of NFTs
in the CNS.
NFTs have not been reported in the visceral autonomic
nervous system in human subjects. Interestingly, however,
phosphorylated tau is deposited in the myenteric plexus in
aged Fischer 344 rats [130].
TDP-43 proteinopathy
TDP-43 is a major component of ubiquitinated inclusions
in ALS and frontotemporal lobar degeneration with or
without motor neuron disease [8, 106]. Thus, these
6 Acta Neuropathol (2010) 120:1–12
123
neurodegenerative disorders comprise a new disease con-
cept, namely that of ‘‘TDP-43 proteinopathy.’’ TDP-43
immunohistochemistry has revealed overt inclusions of
filamentous structures (skein-like inclusions) or compact,
round morphology (round inclusions) in motor and non-
motor neurons in TDP-43 proteinopathy [32, 103]. In
addition, TDP-43-positive inclusions occur both in oligo-
dendrocytes and astrocytes in a considerably wider area in
the CNS [109–111]. TDP-43 deposited in TDP-43 pro-
teinopathy lesions is phosphorylated [53].
Although an absence of sensory disturbances is a
negative neurological sign in sporadic ALS, occasional
reports describing sensory signs and symptoms have been
published [92, 156]. Brownell et al. [26] have reported
that posterior column lesions were observed in 5 out of 45
cases of sporadic ALS. In addition, rare instances of
sporadic ALS with severe involvement of the posterior
column and spinal sensory ganglia have been reported
[167]. However, some of these lesions have been con-
sidered an incidental complication due to spondylotic
myelopathy or circulatory disturbance. Recent studies
have revealed that abnormal accumulation of TDP-43
occurs in the dorsal root ganglia but not in the peripheral
sympathetic ganglia in patients with sporadic ALS [110].
Nishihira et al. [110] found mild neuronal loss in the
dorsal root ganglia in 10 out of 35 patients with sporadic
ALS, two of whom showed TDP-43-positive neuronal
cytoplasmic inclusions in the ganglia. TDP-43-immuno-
reactive LB-like inclusions have also been described in
the dorsal root ganglia in a patient with ALS after long-
term survival on a respirator [111]. Sensory involvement
may occur with greater frequency in sporadic ALS than
previously thought.
TDP-43 is a nuclear transcription factor and TDP-43
immunohistochemistry shows diffuse nuclear staining in
unaffected neurons. However, in neurons with well-formed
inclusions, such as skein-like and round inclusions, nuclear
TDP-43 immunoreactivity is absent. Recently, Suzuki et al.
[150] performed a quantitative immunohistochemical study
of TDP-43 in the skin from patients with ALS (n = 15) and
control subjects (n = 15). The proportion and optical den-
sity of TDP-43-positive nuclei in the epidermis were
significantly higher in ALS than in controls. In addition,
there was a significant positive relationship between the
nuclear staining and disease duration in ALS patients. TDP-
43 protein in the plasma [46, 47] and cerebrospinal fluid
[69] may be a potential biomarker of TDP-43 proteinopa-
thy, and skin biopsy may be useful for the diagnosis of ALS.
Bunina bodies are small round eosinophilic inclusions
observable in the lower motor neurons in ALS. They are
thought to originate from the endoplasmic reticulum [151,
159]. Piao et al. [132] have reported the presence of Bunina
bodies in 88 out of 102 patients with ALS (86.3%).
However, such inclusions have not hitherto been reported
in the PNS.
Polyglutamine disease
The expansion of a CAG repeat that codes for polyglutamine
is a common gene mutation in hereditary neurodegenerative
disorders [178]. Recent immunohistochemical studies of
human and animal models of polyglutamine diseases have
shown that neuronal and glial nuclear abnormalities extend
to multiple central and peripheral areas of the nervous sys-
tem, far beyond the affected regions that have been reported
in conventional pathological studies [56, 180]. Immuno-
histochemistry for expanded polyglutamine stretches have
demonstrated that neuronal intranuclear inclusions are
present in the dorsal root ganglia and paravertebral and
celiac sympathetic ganglia in spinocerebellar ataxia type 3
(Machado-Joseph disease) [179], but not in dentatorubral-
pallidoluysian atrophy [181] or spinal and bulbar muscular
atrophy [90]. Moreover, formation of polyglutamine inclu-
sions have been reported in non-CNS tissue in a mouse
model of Huntington’s disease [139] and patients with spinal
and bulbar muscular atrophy [90].
Conclusions
Neurodegenerative proteinopathies are multisystem disor-
ders including the PNS. Further elucidation and
characterization of the PNS lesions will provide implica-
tions for intravital biopsy diagnosis in neurodegenerative
proteinopathy, particularly in LB disease. Future studies
are necessary to identify novel biomarkers and proteins for
the diagnosis and for assessing disease progression of
neurodegenerative disorders.
Acknowledgments This work has been supported by Grants-in-Aid
20300123 (K.W.), 20591361 (F.M.) and 20590335 (K.T.) for Scien-
tific Research from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan, a Grant for Hirosaki University
Institutional Research (K.W.), and a Grant-in-Aid for Studies on the
Development of Diagnostic Technique and Therapies for Lewy Body
Disease, the Ministry of Health, Labour and Welfare, Japan (K.W.).
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