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Brainstem pathology in DYT1 primary torsion dystonia.

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Brainstem Pathology in DYT1 Primary
Torsion Dystonia
Kevin St. P. McNaught, PhD,1 Alexander Kapustin, PhD,1 Tehone Jackson, BSc,1 Toni-Ann Jengelley, BSc,1
Ruth JnoBaptiste, BA,1 Pullanipally Shashidharan, PhD,1 Daniel P. Perl, MD,2 Pedro Pasik, MD,1
and C. Warren Olanow, MD1
DYT1 dystonia is a severe form of young-onset dystonia caused by a mutation in the gene that encodes for the protein
torsinA, which is thought to play a role in protein transport and degradation. We describe, for the first time to our
knowledge, perinuclear inclusion bodies in the midbrain reticular formation and periaqueductal gray in four clinically
documented and genetically confirmed DYT1 patients but not in controls. The inclusions were located within cholinergic
and other neurons in the pedunculopontine nucleus, cuneiform nucleus, and griseum centrale mesencephali and stained
positively for ubiquitin, torsinA, and the nuclear envelope protein lamin A/C. No evidence of inclusion body formation
was detected in the substantia nigra pars compacta, striatum, hippocampus, or selected regions of the cerebral cortex. We
also noted tau/ubiquitin-immunoreactive aggregates in pigmented neurons of the substantia nigra pars compacta and
locus coeruleus in all four DYT1 dystonia cases, but not in controls. This study supports the notion that DYT1 dystonia
is associated with impaired protein handling and the nuclear envelope. The role of the pedunculopontine and cuneiform
nuclei, and related brainstem other involved brainstem structures in mediating motor activity and muscle tone also
suggest that alterations in these structures, in mediating motor activity and controlling muscle tone suggests that alterations in these structures could underlie the pathophysiology of DYT1 dystonia.
Ann Neurol 2004;56:540 –547
Primary torsion dystonias (PTDs) are neurological disorders that characterized by involuntary, repetitive or
sustained, twisting, muscle contractions that can affect
the limbs, head, neck, and/or torso.1 Thirteen hereditary types of PTD have been identified and designated
DYT1 to DYT13.1 DYT1 dystonia (also known as
dystonia musculorum deformans and Oppenheim’s
disease) is a particularly severe form of PTD with an
age of onset of younger than 26 years and an autosomal dominant pattern of inheritance with a 30 to 40%
rate of penetrance.1
DYT1 dystonia is caused by a GAG deletion in the
DYT1 gene at chromosome 9q34.2,3 This mutation
leads to the deletion of a single glutamic acid residue
near the C terminus of the 332–amino acid protein
torsinA.2,3 TorsinA is widely expressed in neurons
throughout the central nervous system with particularly
high levels in the brainstem.4 –7 The normal function
of torsinA remains unknown. It has sequence homology with AAA⫹ proteins (ATPases associated with a
variety of cellular activities) which is a superfamily of
molecular chaperones (heat shock proteins) and pro-
teases that mediate protein transport, folding, and degradation.3,6 Thus, it is reasonable to consider that
torsinA might play a role in protein trafficking and
clearance.3,6,8 Indeed, overexpression of wild-type
torsinA protects cultured cells from a variety of toxic
insults associated with protein accumulation and inclusion body formation, whereas this benefit is not observed with overexpression of mutant torsinA.9 Therefore, DYT1 dystonia might be associated with protein
accumulation and inclusion bodies as seen in other
neurodegenerative disorders related to altered protein
handling.10,11 However, histopathological studies of
DYT1 brains, while few in number, have not found
evidence of protein accumulation or inclusion bodies.5,12 This may reflect the sensitivity of the antibodies
used and examinations limited to unaffected brain regions. In this study, we used novel antibodies that are
highly sensitive in detecting ubiquitinated proteins and
inclusion bodies13 to examine brains from four clinically documented and genetically confirmed cases of
DYT1 dystonia. We demonstrate, for the first time to
our knowledge, the presence of perinuclear inclusions
From the Departments of 1Neurology and 2Pathology, Neuropathology Division, Mount Sinai School of Medicine, New York, NY.
Address correspondence to Dr McNaught, Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-73, One
Gustave L. Levy Place, New York, NY 10029.
Received Apr 7, 2004, and in revised form May 19. Accepted for
publication Jun 15, 2004.
Published online Sep 30, 2004, in Wiley InterScience
( DOI: 10.1002/ana.20225
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Table. Dystonia and Control Cases Studied in This Investigation
Age When
Age at
not available
Patient 4
Control 1
Control 2
Dystonia musculorum deformans
(typical DYT1
Focal nonprogressive
Dystonia musculorum deformans
(typical DYT1
Generalized dystonia
Control 3
Control 4
not available
Pancreatic carcinoma
Patient 1
Patient 2
Patient 3
Cause of
PMI (hr)
None of the above DYT1 and control cases exhibited clinical or pathological evidence of other neurodegenerative disorders. Drug history was
available for DYT1 patients.
PMI, postmortem interval.
in cholinergic and other neurons of the midbrain reticular formation (particularly the pedunculopontine nucleus [PPN], the cuneiform nucleus [CN]) and periaqueductal gray (PAG). These brainstem regions have not
been implicated previously in DYT1 dystonia and provide a basis for better understanding the pathophysiology of the illness and developing new therapeutic strategies.
Materials and Methods
Brain Tissues
We studied brains from four clinically documented and genetically confirmed cases of DYT1 dystonia, and from four
control subjects without clinical or pathological evidence of
neurological illness (Table). Brain tissues from DYT1 dystonia Patients 1 to 3 and Controls 1 to 2 were obtained from
the Harvard Brain Tissue Resource Center (McLean Hospital, Belmont, MA). Brain tissues from DYT1 dystonia Patient 4 and Controls 3 and 4 were obtained from the Department of Pathology at the Mount Sinai School of
Medicine. Fresh-frozen and formalin-fixed (10%)/paraffinembedded blocks of cerebral cortex, hippocampus, striatum,
midbrain, and pons were provided. Genetic screening for
GAG deletion was performed by reverse transcription polymerase chain reaction (RT-PCR) as previously reported
(Fig 1).5,12
Primary Antibodies
Antibodies that are highly sensitive to, and preferentially recognize ubiquitin-protein conjugates (UPCs) with little or no
reactivity to free ubiquitin, were obtained from Affiniti Research Products Ltd (UG9510, polyclonal; Exeter, UK). The
production and immunoreactivity of this antibody have been
described elsewhere.13,14 We used mouse monoclonal
(MAB1510; Chemicon International, Temecula, CA) and
rabbit polyclonal (Z0458; DakoCytomation, Carpinteria,
CA) antibodies to ubiquitin (UBQ). We used antibodies to
␣-synuclein, lamin A/C, microtubule associated protein–2
(MAP-2), choline acetyl transferase (ChAT), glial fibrillary
acidic protein (GFAP), the serotonin transporter and tau
(Chemicon International), ␤-amyloid (Signet Laboratories,
Dedham, MA), and protein disulfide isomerase (PDI; Stressgen Biotechnologies, San Diego, CA). Polyclonal (rabbit) antibodies to torsinA were prepared by us as previously described.6 Antibody specificity was confirmed by labeling
bands of appropriate molecular weights on Western blots
and/or from the lack of staining on blots and tissue sections
in the absence of primary antibodies or following preadsorption with cognate proteins (Fig 2U, V).6,13
Sections (5␮m-thick) were cut and mounted onto glass slides
and stained using a standard Vector ABC immunostaining
procedure with 3,3⬘ diaminobenzidine hydrochloride (DAB)
chromogen.13 Sections were counterstained with either hematoxylin or toluidine blue. Double immunofluorescence
was conducted using Alexa Fluor 488 and Alexa Fluor 594
secondary antibodies (Molecular Probes, Eugene, OR) with
the bisbenzimide (Hoechst 3358) nuclear dye.13
Protein Accumulations and Inclusion Bodies
In each of the four DYT1 patients, protein accumulations, and inclusion bodies, which stained positively for
UPC (see Fig 2F–H), UBQ (see Fig 2L–N), and
torsinA (see Fig 2R–T), were observed in cells located
McNaught et al: Neuropathology in DYT1 Dystonia
Fig 1. Demonstration of a GAG deletion in patients with clinical evidence of DYT1-linked primary torsion dystonia. Total
RNA was isolated from brain tissue obtained from normal subjects (control) and DYT1 patients and were subjected to reverse
transcription polymerase chain reaction (RT-PCR). The PCRamplified product was digested with BseR1 restriction enzyme.
Lane 1 shows RT-PCR products after digestion with BseR1
from control brain tissue, and lane 2 shows RT-PCR products
after digestion with BseR1 from DYT1 brain tissue. Digestion
of PCR products from the normal cDNA yields DNA fragments
of 24 bp, 94 bp, 95 bp fragments which co-migrate on the
agarose gel. In contrast, the mutant cDNA yields DNA fragments of 95 bp and 118 respectively due to the loss of BSCRI
restriction site. Results from DYT1 Patient 4 are shown and are
representative of the other three DYT1 cases.
in the midbrain and pontine reticular formation (RF)
and PAG (see Fig 2). Inclusion bodies were detected in
cells at the caudal level of the superior colliculus and
the rostral level of the pons in regions anatomically localized to the PPN, CN, and the griseum centrale mesencephali (see Fig 2A, B). Colocalization studies
showed that inclusion bodies were immunoreactive for
both ubiquitin and torsinA (Fig 3B). Inclusion bodies
were predominantly perinuclear and frequently appeared to abut upon or indent and compress the nucleus (see Fig 2). The inclusions did not stain for
␣-synuclein (data not shown). There was a marked difference in the ability of the various antibodies to detect
areas of protein accumulation and inclusion bodies,
with the UPC antibody being more sensitive than the
UBQ and torsinA antibodies (see Fig 2). For example,
in the low-powered microscopic field of the midbrain
RF (see Fig 2), six cells containing inclusion bodies
were seen with UPC antibodies (F), but only one to
two cells were detected with UBQ (L) or torsinA (R)
antibodies. This finding is consistent with previous investigations showing that the UPC antibody is more
Annals of Neurology
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October 2004
sensitive than UBQ antibodies in detecting protein accumulation and Lewy body formation in Parkinson’s
disease and dementia with Lewy bodies.13
We used a multiple immunofluorescence staining
protocol using antibodies to UBQ and microtubule associated protein–2 (MAP-2) to show that the inclusion
bodies were present within neurons (see Fig 3A). These
inclusions colocalized with the cholinergic marker choline acetyl transferase (ChAT), but not with serotoninergic (serotonin transporter), dopaminergic (tyrosine
hydroxylase), or astrocytic (glial fibrillary acidic protein) markers (see Fig 3A). Inclusions had little or no
immunoreactivity for protein disulfide isomerase, a
marker of the endoplasmic reticulum, but stained intensely for lamin A/C, a marker of the nuclear envelope (see Fig 3C).
No inclusion bodies were detected in the cerebral
cortex, hippocampus, substantia nigra pars compacta
(SNc) or striatum of patients with DYT1 dystonia
(data not shown). In contrast with the findings in
DYT1 patients, no protein accumulations or inclusion
body formation was detected in the brainstem or in
any other brain region in any of the control brains (see
Fig 2).
Tau- and Ubiquitin-Positive Protein Aggregates
In each of the four DYT1 cases, there were tau- and
ubiquitin-positive immunoreactive protein aggregates
located in the soma and processes of some pigmented
cells of the SNc and locus coeruleus (LC) (Fig 4).
These did not stain for torsinA. No tau or ubiquitinimmunoreactive aggregates were detected in other
brainstem regions, striatum, hippocampus, or the cerebral cortex, although we did not have tissue to study
the entorhinal cortex or nucleus basalis of Meynert. No
amyloid plaques were observed in any of the brain areas examined. In contrast with the findings in the
DYT1 patients, no tau- or ubiquitin-positive immunoreactive inclusions were detected in the SNc, LC, or
other regions examined in the brains of any of the
control cases.
We demonstrate for the first time to our knowledge,
the presence of ubiquitin/torsinA-immunoreactive inclusions in neurons located in various brainstem structures, and particularly in neurons of the PPN, CN, and
PAG in patients with DYT1 dystonia. No such
changes were noted in other brain regions studied nor
in any of the controls. However, because we had only
limited tissue, we could examine only sections taken at
several levels rather than through the entire brainstem.
Thus, we could not determine if inclusions bodies were
present in other brain areas or if there was neuronal
The occurrence of protein accumulation and inclu-
Fig 2. Staining of brainstem sections in DYT1 and control subjects. (A, B) These are coronal sections of the RF from one of the
DYT1 brains which we stained for myelin using a conventional Luxol fast blue protocol. (A) Caudal level of the superior colliculus.
(B) Rostral level of the pons. RN ⫽ red nucleus; SNc ⫽ substantia nigra pars compacta; RF ⫽ reticular formation; LC ⫽ locus coeruleus; PAG ⫽ periaqueductal gray; PPN ⫽ pedunculopontine nucleus; CN ⫽ cuneiform nucleus. Scale bar (A, B) ⫽ 7.5mm. (C–V)
A standard Vector ABC immunostaining procedure with DAB chromogen (brown) and hematoxylin counterstain for nuclei (blue), in
conjunction with antibodies to ubiquitinated proteins (C–H), ubiquitin (I–N), and torsinA (O–T), was used to determine if these
proteins accumulate and form inclusions bodies in the brain in all DYT1 dystonia cases compared with controls. Arrows point to perinuclear/intranuclear protein accumulation and inclusion body formation. Panels U and V demonstrate the lack of immunostaining in
the absence of primary antibodies in a control and DYT1 dystonia brain section. Scale bar (C, F, I, L, O, R, U, V) ⫽ 40␮m. Scale
bar (D, E, G, H, J, K, M, N, P, S, T) ⫽ 5␮m: Scale bar (Q) ⫽ 5␮m.
McNaught et al: Neuropathology in DYT1 Dystonia
Fig 3. Colocalization of proteins in intracellular inclusions in midbrain sections of DYT1 dystonia. A fluorescent-based immunostaining protocol was used to stain post-mortem midbrain sections from all DYT1 and normal control cases. Red, green, and blue
fluorescence represent proteins labeled with Alexa Fluor 594, proteins marked with Alexa Fluor 488, and cell nuclei stained with
bisbenzimide (Hoechst 3358), respectively. (A) Demonstration that the ubiquitin (UBQ)/torsinA–positive inclusions are present in
neurons that stain for microtubule-associated protein–2 (MAP-2) and choline acetyltransferase (ChAT). Scale bar ⫽ 10␮m. (B)
The perinuclear/intranuclear inclusion bodies stain for both ubiquitin and torsinA. Scale bar ⫽ 10␮m. (C) Demonstration that
the ubiquitin/torsinA-immunoreactive inclusions (arrows) stain lightly for the endoplasmic reticulum (ER) marker protein disulfide
isomerase (PDI) but stain intensely for the nuclear envelope (NE) protein lamin A/C. Note the normal and characteristic staining
of the ER and NE in cells that do not contain inclusion bodies. Scale bar ⫽ 20␮m.
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Fig 4. Tau- and ubiquitin-positive protein aggregates in the locus coeruleus (LC) and substantia nigra pars compacta (SNc) in
DYT1 dystonia. Immunostaining of the LC (A–C) and SNc (D) using a standard Vector ABC staining procedure with DAB chromogen (brown/black) in conjunction with antibodies to ubiquitin (A, B) or tau (C, D), and hematoxylin/toluidine counterstain. All
panels are from DYT1 dystonia Patient 4. In panel A, neuromelanin-pigmented cells containing tau/ubiquitin-immunoreactive aggregates are indicated by arrows. Panels B is a higher magnification of the cell identified in panel A by the asterisk. Scale bar in
A ⫽ 40␮m, in B–D ⫽ 10␮m.
sion body formation in the brainstem of patients with
DYT1 dystonia is consistent with the finding that
torsinA is normally highly expressed in this brain area.7
In addition, our findings support the notion that
torsinA might normally play a role in protein (re)folding, degradation, and transport.3,6,8 Indeed, overexpression of wild-type torsinA in cultured cells prevents
protein aggregation and protects against cytotoxicity after proteasomal inhibition, oxidative stress, or trophic
factor withdrawal.9,15,16 In contrast, expression of mutant torsinA fails to protect cells from these toxic insults and leads to the formation of perinuclear inclusion bodies.9,17–19 The association of the inclusions
with the nuclear envelope in patients with DYT1 dystonia but not controls fits well with the observation
that wild-type torsinA is prominently found in the endoplasmic reticulum, whereas the mutant protein is
preferentially expressed in relation to the nuclear envelope.17,18,20 –23 Indeed, in cultured cells, mutations in
torsinA promote the translocation of the protein from
the endoplasmic reticulum to the nuclear envelope.19,22,23 The presence of inclusions in proximity to
the nuclear envelope in DYT1 dystonia raises the possibility that mutations in torsinA could act to disrupt
the integrity and function of this structure. Thus, mu-
tations in torsinA could alter a variety of intracellular
processes which might underlie neuronal dysfunction
and/or neurodegeneration in DYT1 dystonia.
The findings in this study suggest that pathologies in
one or more nuclei of the brainstem, in particular the
PPN, CN, and PAG, could underlie the pathophysiology of DYT1 dystonia. The PPN and CN are known
to play important roles in motor activity by way of
extensive afferent and efferent connections with motor
areas of the cerebral cortex, basal ganglia, and spinal
cord.24 –27 The PPN receives major inputs from the
globus pallidus pars interna (GPi), subthalamic nucleus
(STN), and the substantia nigra pars reticulata (SNr).
Projections from PPN terminate in thalamic and basal
ganglia regions, especially the SNc and STN, as well as
in the lower brainstem, cerebellar nuclei, and spinal
cord.24 –27 The PPN and CN together constitute the
mesencephalic locomotor region which is thought to
regulate muscle tone and rhythmic limb movements
during locomotion.24 –27 The PAG is also thought to
be functionally associated with the mesencephalic locomotor region.26 A reduction in the number of PPN
neurons has been reported in Parkinson’s disease,28,29
and lesions of the PPN in experimental animals induce
akinesia and a parkinsonian-like state.30 On the other
McNaught et al: Neuropathology in DYT1 Dystonia
hand, electrical stimulation of the PPN elicits locomotor activity in experimental animals and may increase
or decrease muscle tone depending on frequency.31,32
Indeed, stimulation of the PPN region in a human
subject has been reported to cause increased muscle
tone in the contralateral limb.33
The significance of the tau- and ubiquitin-positive
protein aggregates in the SNc and LC of the DYT1
patients is not known. Neurofibrillary tangles often
are seen in elderly individuals, but the tau- and
ubiquitin-positive inclusions we saw in our DYT1 patients were not seen in any of our controls. Furthermore, we saw the same tau- and ubiquitin-positive
inclusions in one of our DYT1 patients who was only
33 years of age. A previous study reported neurofibrillary tangles in neurons of the LC, SNc, PPN, and
raphe nucleus of a 29-year-old patient with dystonia
musculorum deforms.34 The fact that none of our patients had clinical or pathological evidence of Alzheimer’s disease or another tauopathy and the relatively
young age of one of our patients, suggest that the
appearance of tau- and ubiquitin-positive aggregates
could be related to mutations in torsinA.
In conclusion, our study raises the possibility that
DYT1 dystonia is a protein handling disorder and supports a role for the nuclear envelope as seen in experimental studies. It also suggests that neuronal dysfunction or death in brainstem nuclei could underlie the
pathophysiology of DYT1 dystonia.
This study was supported by grants from the Bachmann-Strauss
Dystonia and Parkinson Foundation Inc., (K.M., C.W.O.) the
Bendheim Parkinson’s Disease Center (K.M.), the Schapiro Foundation (K.M., C.W.O.), and the NIH (National Institute of Neurological Disorders and Stroke, 1 RO1 NS045999-01 K.M.,
C.W.O., D.P.).
We gratefully acknowledge the Harvard Brain Tissue Resource Center, which is supported in part by PHS grant MH/NS 31862, for
the provision of brain tissues.
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