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Cytoskeletal protein abnormalities in neurodegenerative diseases.

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Cytoskeletal Protein Abnormahties
in Neurodegenerative Diseases
James E. Goldman, MD, PhD,"t and Shu-Hui Yen, PhDX
The nervous system is a rich source of filamentous proteins that assume critical roles in determining and maintaining
neuronal form and function. Neurons contain three major classes of these cytoskeletal organelles: microtubules,
intermediate filaments, and microfilaments. They also contain a variety of proteins that organize them and serve to
connect them with each other. Such major neurodegenerative diseases as Alzheimer's disease, Parkinson's disease, and
amyotrophic lateral sclerosis, as well as a variety of toxic neuropathies, are characterized pathologically by intraneuronal filamentous inclusions. Recent studies using biochemical and immunocytochemical techniques have established that these abnormalities represent disorganized states of the neuronal cytoskeleton and have determined some of
the specific molecular constituents of these inclusions. This knowledge has led to new ways of thinking about their
Goldman JE, Yen S-H: Cytoskeletal protein abnormalities in neurodegenerative diseases.
Ann Neurol 19209-223, 1986
Neurodegenerative diseases comprise a large number
of disorders characterized by loss of neurons in various
areas of the central nervous system. Besides neuronal
death, these diseases are characterized pathologically
by the formation of abnormal inclusions within nerve
cells. A number of such abnormalities, such as the
neurofibrillary tangles of Alzheimer's disease and the
Lewy bodies of Parkinson's disease, were first noted
many decades ago and still represent neuropathological
hallmarks of these disorders. While neurologists and
neuropathologists have observed these lesions for
many years and have long recognized their diagnostic
value, only recently has anything been learned about
the specific molecular composition of these structures.
Many of the most common inclusions turn out to be
closely related to the major filamentous proteins of
neurons, either representing profoundly abnormal arrangements of normal cytoskeletal structures or representing altered filamentous organelles.
Since the original histological descriptions of the
various inclusions, there have been two major phases
in our understanding of their composition. The first
occurred in the 1960s, when brain biopsies and autopsy material were examined under the electron microscope. A number of important studies revealed, for
the first time, d e n t details of structural organization
and determined the filamentous nature of many of the
abnormalities. Research and review articles at the time
naturally stressed the ultrastructural qualities of these
abnormalities, but were able to offer only conjecture
as to their composition 1117, 1397. The second phase
has taken place within the last several years, during
which time some of the molecular constituents of
these inclusions have been determined. These insights
have been made possible by our far more sophisticated
knowledge about the normal cytoskeletal elements of
neurons and by the availability of new approaches and
reagents, especially polyclonal and monoclonal antibodies to a host of cytoskeletal proteins that are being
used with great success as specific molecular probes.
Furthermore, it has been possible to begin to place
these abnormalities into a framework of neuronal cell
biology and to begin to think about how they form.
In this review, we will trace the evolution of our
knowledge of these abnormalities, summarize current
information about their composition, and provide
our perspectives on future research and on how
our knowledge may be used to illuminate abnormal
neuronal metabolism in neurodegenerative states.
From the Departments of *Pathology (Neuropathology) and
tNeuroscience, Albert Einstein College of Medicine, Bronx, N Y
Received July 10,1985, and in revised form Aug 15. Accepted for
publication Aug 16, 1985.
Address reprint requests to Drs Goldman or Yen.
Normal Cytoskeletal Elements of Neurons
Neurons, like most other cells, contain three major
polymeric protein systems that have important roles in
determining and maintaining cell shape, allowing cell
motility, and moving molecules and organelles about
within the cytoplasm. In discussing these cytoskeletal
systems and their disorders, we must consider the
three components of each system: microtubules, intermediate filaments, and microfilaments, as well as the
interconnections that link these systems together.
M icrotubules
Microtubules are hollow, cylindrical structures, 24 nm
in diameter. They are long, unbranched organelles
found in abundance in both axons and dendrites,
where they are oriented along the long axis of the
process, They are composed of two closely related
globular proteins, alpha and beta tubulin, with molecular weights of 54 kDa and 56 kDa. Tubulins exist in
both polymerized (microtubular) and unpolymerized
forms. The equilibrium between forms can be altered
in vitro by a number of agents, including calcium,
which depolymerizes microtubules; temperature; tubulin concentration; and drugs such as colchicine,
which depolymerizes microtubules, and taxol, which
stabilizes microtubules 1114, 115). These drugs can
also affect states of tubulin polymerization in vivo.
Microtubules interact with other organelles by way
of thin side arms. These side arms are composed of a
variety of proteins that have been termed microtubuleassociated proteins (MAPs) because they co-purify with
microtubules during several types of isolation procedures [11, 22, 1471. The major MAPs are highmolecular-weight proteins (MAPl, 350 kDa; MAP2,
270 kDa); each of these has been further divided into
subgroups on the basis of molecular weights and antigenic reactivities 1147). A group of smaller MAPs, the
tau proteins, have molecular weights in the range of 5 5
to 65 kDa 1221. MAPs also interact in vitro with
neurofilaments 179, 1101 and with actin filaments 152,
86, 113, 123). The high-molecular-weight MAPs are
phosphoproteins, substrates for a cyclic-adenosine
monophosphate (CAMP)-dependent protein kinase activity that is present in microtubule and MAP preparations from brain 1130, 141). Both CAMP-dependent
and CAMP-independent phosphorylation 1141) and
calciumlcalmodulin-dependent phosphorylation 1120)
may occur in vitro. The idea that phosphorylation may
regulate the interaction of MAPs (and therefore microtubules) with other organelles is an attractive one,
and is given some plausibility by the fact that MAP2
interactions with actin in vitro are sensitive to states of
phosphorylation 186, 1231. Studies with antibodies to
specific MAP species have indicated that neurons distribute MAPs differentially within cytoplasmic compartments. For example, MAPla, one of the very highmolecular weight proteins, and MAP2 are found
primarily in dendrites and neuronal cell bodies,
whereas MAPlb, distinguished from MAPla by
molecular weight and by immunological means, can be
detected in both axons and dendrites [9, 17, 26, 82).
Intermediate Filaments
Neurofilaments (NFs) are part of a class of
intermediate-filament (IF) proteins, all forming polymers about 10 nm in diameter 1751. Like microtubules, NFs are unbranched structures traveling
210 Annals of Neurology
Vol 19 No 3 March 1986
down the long axis of axons. NFs are predominantly
axonal organelles, although they also reside in proximal dendrites of large neurons. The density of NFs is
approximately constant over a wide range of axon diameters [38]; small axons, such as parallel fibers of the
cerebellar cortex, apparently do not contain NFs. This
observation as well as studies of regenerating axons
suggest that NFs may have a major role in determining
axonal volume 162). IF proteins show cell-type
specificity: keratin-type IFs ate found in epithelial cells;
desmin in muscle; neurofilaments in neurons; glial
fibrillary acidic protein in astrocytes, ependyma, and
some Schwann cells; and vimentin in cells of mesenchymal origin as well as immature cells of many different lineages 175). All of these IF proteins are structurally related, containing a high concentration of acidic
amino acids, and substantial alpha-helical domains separated by sequences that are less highly organized {40].
Amino acid sequences have shown a high degree of
homology among the different IF proteins, particularly
within the helical-rich portion. Carboxy-terminal ends
of the proteins vary more considerably.
Neurofilaments differ from other IFs in that they are
composed of three different proteins, with molecular
weights of approximately 70 kDa, 160 kDa, and 200
kDa 140, 41, 1161, each of which is a separate transcript. The three proteins are related, particularly the
amino-terminal portions, which contain the alpha helical domains [40,41]. The long carboxy-terminal parts
of the larger proteins do not contain alpha-helical domains, and thus appear to be different from the aminoterminal end. It is not surprising, therefore, that there
are anti-NF antibodies, both polyclonal and monoclonal, that bind to one, two, or all three NF proteins.
The various cross-reactivities of different antibodies
have been a source of confusion, and emphasize the
critical point that antibody reactivities need to be
defined as fully as possible before interpreting the results of immunocytochemical studies. There is evidence that the 70 kDa NF protein and the corresponding amino-termini of the others can form the
core of the filament, and that the long carboxy-termini
of the large NF proteins project from the filaments
Microtubule-associated proteins bind to IFs, including NFs, in vivo and in vitro 110, 79, 957. Their interactions must be kept in mind when one considers
several pathological states in which NFs appear to be
disconnected from microtubule systems (as will be discussed later).
Unlike tubulin and actin, which exist in polymerized
and nonpolymerized forms, IFs exist largely or entirely
in polymerized form. They can be solubilized, but solubilization requires ionic detergents such as sodium
dodecyl sulfate (SDS) or other chaotropic agents.
IF proteins are phosphoproteins. The 150 kDa and
200 kDa N F components are much more highly phosphorylated than either the 70 kDa NF or the other
classes of IF proteins C68, 69, 1351. The majority of
phosphorylation sites appear to reside on NF domains
away from the alpha-helical core region. Thus, phosphorylation sites reside on parts of the N F molecules
that project from the N F core. It is likely that states of
phosphorylation may affect the interaction of NFs with
other cytoskeletal organelles. States of phosphorylation may also regulate the association of NF proteins
with each other 1162). Enzyme systems that phosphorylate and dephosphorylate NF proteins have not
been well defined. Protein kinase activity has been
isolated, along with partially purified NF proteins
11091 and partially purified microtubules and MAPS,
although what enzymatic mechanism catalyzes phosphorylation in vivo is not known exactly.
The distribution of phosphorylated and nonphosphorylated NF proteins appears to differ within a
neuron, as assessed using anti-NF monoclonal antibodies that react with phosphorylated versus nonphosphorylated epitopes C1361. Nonphosphorylated
sequences are detected in neuronal cell bodies and
proximal axons, while phosphorylated sequences are
found in axons and preterminal processes. These immunocytochemical studies do not exclude some phosphorylated sites on somal NFs, since these may be
phosphorylated epitopes that are not recognized by
the antiphosphorylated NF antibodies. What properties phosphorylation confers upon NFs remains an important question.
M icrojdaments
Microfilaments, 5 nm in diameter, are the smallest of
the major cytoskeletal filaments and are composed of
actin polymers. The central nervous system is a rich
source of proteins such as actin and myosin that have
been known for years to be the major components of
muscle contractile systems. Actin is widely distributed
within the neuron, with particular concentration of
microfilaments just beneath the plasma membrane, at
postsynaptic densities, and within dendritic spines 117,
20, 31,47, 771. Much of the actin in the brain exists in
nonfilamentous form (G, or globular actin, as opposed
to F, or filamentous actin) C131, but what determines
the equilibrium between G and F actin in neurons is
not known. In both central nervous system and noncentral nervms system cells, there are a variety of actin-binding proteins, some of which serve to polymerize actin, others to cap an end of the filament and
retard either polymerization or depolymerization, and
others to bind G actin and prevent its polymerization
18, l50}. These proteins probably have major roles in
determining polymerization states. In addition to actin,
other contractile system proteins found in the central
nervous system include myosin, tropomyosin [14, 321,
and spectrin-like molecules {4, 761. Conditions that
alter states of actin polymerization or alter the interaction of actin with binding proteins could in turn change
neuronal shape considerably, or cause the formation of
abnormal filamentous aggregates (see below).
Axonal Transport of Cytoskeletal Systems
Since a neuron’s cell body is the primary site of protein
synthesis, special mechanisms have evolved to carry
molecules into axons and dendrites. Membranous organelles are transported at fast rates, on the order of
400 mm per day in poikilotherms. Cytoskeletal proteins, in contrast, move slowly along axons. Metabolic
labeling experiments, using radioactive amino acids,
have delineated two major components to slow transport, which can be distinguished not only by their differences in rates but also by differences in the specific
molecules moving at those rates 16, 63, 1531. The
faster of the two components moves at 2 to 5 mm per
day, although rates vary somewhat among particular
nerves and species. This system includes actin, myosin,
and a variety of other proteins such as clathrin and
calmodulin 16, 12}. The slower component moves at
0.25 to 2 mm per day. This component includes all
three NF proteins. Most tubulin appears also to move
with NFs at the slower rate, but some tubulin is more
widely distributed in its transport profile. The fact that
a number of proteins in each of the slow transport
systems are transported together has been taken as
evidence for the presence of functional connections
among the individual components 161. The idea that
proteins within transport systems are linked is illustrated by the fact that such linkages can be disrupted.
Several neurotoxins, such as aluminum and p-p’iminodipropionitrile (IDPN) (as will be discussed
later) dissociate the transport of NFs from that of
Cytoskeletal proteins themselves are critically involved in the process of axonal transport. For example,
agents that depolymerize or disrupt microtubules or
actin filaments inhibit fast transport C45, 1213. Thus,
aberrations in cytoskeletal organization may have profound secondary consequences upon the distribution
of macromolecules throughout a neuron’s axonal and
dendritic arborization.
Neurofibrillary Tangles
Neurofibrillary tangles (NFTs), first described by Alzheimer in 1906, are argyrophilic intraneuronal inclusions found in a number of central nervous system
diseases. The most common and best studied NFTs
are composed largely of paired helical filaments (PHFs;
Fig 1A). PHFs are structurally unlike any of the normal cytoskeletal elements, being composed of pairs of
10-nm filaments that cross each other at an 80-nm
Neurological Progress: Goldman and Yen: Neuronal Cytoskeletal Abnormalities 2 11
Fig I. (A) Electron micrograph of paired helicalfilaments, showing the periodic crossover points (arrowheads). ( x 240,000 befire 20% reduction.)(B) Immunocytochemical staining of Alzheime#s disease hippocampus with a monoclonal antibody to
Alzheimer neurofi brillaty tangle, using a peroxidase-antiperoxidase method. In this field, neurojibrilka y tangles (arrowhead)
and thin processes react with the antibody. ( x 280 befire 20%
interval. The maximum width of the PHF is 20 nm,
and the minimum width is 10 nm [158]. PHFs isolated from brain tissue obtained from subjects with
Alzheimer’s disease have been shown by negative
staining with phosphotungstic acid to contain four
protofilaments of 3 to 5 nm {l55). However, morphological studies of extremely thin sections of brain
from patients with Alzheimer’s disease, showed that
PHFs may contain eight protofilaments { 159). Despite
these detailed structural studies, the molecular composition of PHFs has still not been determined (to be
Such NETS are one of the major pathological hallmarks of Alzheimer’s disease, where they are found in
pyramidal neurons of the cerebral cortex and hippocampus and in various brainstem nuclei C24, 611.
They are not specific for Alzheimer’s disease, however, and can be found in cortical and subcortical
neurons of adults with Down’s syndrome [l61], in
brainstem nuclei of patients with postencephalitic parkinsonism 1661, in Parkinson-dementia complex of
Guam 1591, in dementia pugilistica, in neurons of rare
cases of subacute sclerosing panencephalitis and
juvenile neurovisceral lipid storage disease (1601, and
212 Annals of Neurology
VoI 19 No 3 March 1986
in small numbers of hippocampal neurons of normal
elderly people. The concentration of NFTs and
neuritic plaques in Alzheimer’s disease correlates with
the degree of cognitive impairment 17, 151). This type
of NFT exhibits green birefringence when stained with
Congo red, and green fluorescence when stained with
thioflavine S {122, 140). These are nonspecific stains,
which also bind to amyloid, and which may reflect a
prominent P-pleated sheet arrangement in NFTs. Xray diffraction analysis has indicated that PHFs are organized in a @-sheetconformation {71]. Normal NFs
do not bind these dyes. It is important to note that the
term nezlrofibrillay tangle refers to a structure seen at
the light-microscopical level and does not imply a
specific ultrastructural composition. For example,
while most NFI‘s in Alzheimer’s disease are composed
of PHFs, in some tangles straight filaments with a diameter of 15 nm are found occasionally, along with
PHFs E93, 1291.
Biochemical and immunological methods have been
used to examine the molecular structure of NFTs.
However, a major experimental problem in the biochemical analysis of NFTs isolated from brains of patients with Alzheimer’s disease (Alzheimer neurofibrillary tangles, ANTs) has been that the ANTS are
resistant to reagents known to dissolve NFs or other
normal cytoskeletal components, and are insensitive
to various proteolytic enzymes 1125, 126, 168). For
example, the ultrastructure of PHFs treated with
2% SDS is similar to that of control samples. The
insolubility can be used to advantage. A subcellular
fraction greatly enriched in PHFs can be prepared by
removing most of the contaminants with SDS. However, because of their insolubility, the resulting PHFs
cannot be analyzed readily by conventional gel electrophoresis. There is disagreement about whether
small amounts of polypeptides with molecular weights
between 45 and 72 kDa can be released from PHF
fractions after repeated sonication and extraction 1651.
Structural studies of these peptides may give important
clues to the composition of PHFs.
Recently, much work has gone into immunological
analyses, using polyclonal and monoclonal antibodies
raised against a variety of normal cytoskeletal proteins
and against enriched PHF preparations {l, 3, 39, 53,
74, 88, 98, 149, 164, 165, 1661. While most antibodies to normal proteins do not react with ANTs,
some antibodies to N F proteins, MAPS, and vimentin
do. The ANTs do not react with the antiactin or antitubulin antibodies that have been tested to date. In
some studies, not all ANTs in a given tissue section
react with these antibodies, while in others, certain
anti-NF antibodies bind to most tangles. In contrast,
essentially all ANTs react with several of the antibodies raised specifically against ANTs (to be discussed). It is conceivable that phosphorylation or other
biochemical modification, such as covalent crosslinking of proteins or partial proteolysis 187, 1161, may
lead to an alteration or masking of some of the antigenic determinants to NFs and MAPs and the generation of new determinants in ANT. Covalent crosslinking between NFs and cross-linking of NFs to other
intermediate filaments have been demonstrated in
vitro 11241. The resulting structures differ from ANTs
biochemically as well as morphologically, however, although their immunological properties have not been
The antigenic determinants shared by ANTs and
NFs appear to be expressed mostly on the two highmolecular-weight N F proteins (160 kDa and 200 kDa)
11, 3, 1691. We and others 1137) have found that the
antigenic determinants are phosphorylated, and we
find such determinants located at the carboxy-terminal
part of the NF molecules. Since these anti-NF antibodies rarely bind to NFs in normal neuronal cell
bodies (as mentioned earlier), with the inference that
NFs in the neuronal cell body are less phosphorylated
than those in the axon, it is plausible that tangle accumulation may be the result of a disruption of axonal
transport or an alteration in protein kinase or phosphatase activity in the diseased neurons.
Monoclonal antibodies specific to ANTs and polyclonal antibodies to an ANT-enriched preparation
have recently been produced [l5, 53, 149, 1641. They
recognize tangles in cell bodies, stain neurites in
neuritic plaques, and bind to numerous fine neuronal
processes in brains from patients with Alzheimer’s disease in areas where abundant tangles are located (Fig
1B). These antibodies show very little reaction with
normal central nervous system tissues that are devoid
of ANTs. The binding sites in cell bodies, detected by
immunoelectronmicroscopy, are located on PHFs 115,
281. The binding sites in fine processes have not been
examined, however. Since a comparable distribution of
PHFs in fine processes has not been reported in previous morphological studies, it is possible that the antigenic determinants in the processes are on structures
that are not yet fully formed PHFs, and that the antiANT antibodies identify early changes in cytoskeletal
Anti-ANT antibodies have been used to identify
polypeptides in normal brain and in brains from patients with Alzheimer’s disease that might share amino
acid sequences with PHFs. Brain homogenates or
preparations containing a mixture of brain proteins
such as NFs, dial filament proteins, tubulin, and actin
have been separated on polyacrylamide gels by electrophoresis, transferred to nitrocellulose paper, and
then incubated with antibodies. Using this immunoblotting technique, one polyclonal and four monoclonal anti-ANT antibodies were shown to recognize
antigenic determinants unique to ANTs 1105, 149,
1641. In our studies, four additional anti-ANT monoclonal antibodies reacted with polypeptides with
molecular weights of 58 to 70 kDa that are present in
both diseased and normal brains and are soluble in a
buffer containing 50 mM Tris. A polyclonal anti-ANT
antiserum recognized SDS-soluble polypeptides with
molecular weights of 45 to 70 kDa in brains from
patients with Alzheimer’s disease. These polypeptides
are minor components of both normal and diseased
brain homogenates.
The results of biochemical and immunological studies indicate that ANTs are composed of many components, some of which share amino acid sequences with
NFs, MAP2, vimentin, polypeptides of molecular
weights 42 to 70 kDa, and perhaps other unidentified
brain proteins, but some of which are unique. The
determinants shared with normal proteins may well
mean that ANTs are initially formed from NFs and
MAPs and thus retain some of the normal amino acid
sequences. The unique antigenic determinants could
be generated either by posttranslational modification
of normal proteins such as NFs and MAPs or by synthesis of new proteins in brain from Alzheimer’s disease patients. Comparative studies of proteins synthesized in vitro by messenger ribonucleic acid from
normal and diseased brain have not detected new proteins 1112). Nevertheless, the question of how ANTs
are generated still remains a central, unresolved problem.
NFTs composed of PHFs found in diseases other
than Alzheimer’s are also recognized by anti-NF and
anti-ANT antibodies C28, 39, 1061, suggesting that the
PHFs of many diseases are similar, or identical, to
those of Alzheimer’s disease. Further analysis with
biochemical methods is necessary to arrive at firmer
NFTs containing bundles of 15-nm straight filaments are found in the basal ganglia, brainstem, and
deep cerebellar nuclei of patients with progressive supranuclear palsy 11341. PHFs with a periodicity longer
than the classic PHF of Alzheimer’s disease coexist
with the straight filaments in some tangles 11633. The
possibility that NFTs with different morphological
characteristics may be derived from common components has been tested by immunocytochemical staining
with antibodies that bind ANT 128, 167). These studies showed that NFTs from progressive supranuclear
palsy and Alzheimer’s disease do indeed share amino
acid sequences. Furthermore, immunoelectron microscopy revealed that the binding sites for anti-ANT antibodies are located on the 15-nm straight filaments.
Our current view is that PHFs and the straight
filaments are morphological variants constructed from
the same or related polypeptides.
PHFs with a periodicity shorter than that of classic
PHFs have been found in an aged monkey [l56], a
Neurological Progress: Goldman and Yen: Neuronal Cytoskeletal Abnormalities 2 13
Wistar-Kyoto rat 1721, wobbler mice 11561, a whip
spider 1331, and several aged Louvain Wistar rats
11481. The relationship between human and nonhuman PHFs is unknown. Because ultrastructurally distinct NFTs may share antigenic determinants, it is possible that PHFs found in non-human tissues represent
yet another morphological variant of human PHFs.
Pick Bodies
Pick bodies are round, cytoplasmic inclusions characteristic of Pick‘s disease 116, 100, 1541. The lesions
appear most abundantly in the cerebral cortex but are
also found in basal ganglia and other subcortical structures. They contain aggregates of straight filaments of
various diameters ranging from 10 to 20 nm 11071. In
some cases, the filaments are admixed with granular
material; in others, PHFs with a periodicity longer than
that of classic PHFs are found in the same inclusion
with straight filaments. Immunocytochemical studies
have revealed the presence of N F antigens in Pick
bodies 128, 39,84, 104). Those Pick bodies containing
filaments coated with granular material appear less
reactive with anti-NF antibodies and with silver stain
than those containing PHFs 1841. Whether the antibody binding site or sites were inaccessible to the antibody because of the coating is unknown. Crossreactivity of Pick bodies with a commercially available
antitubulin antiserum has also been observed @4}.
However, this antiserum, in addition to tubulin, reacts
with MAPS and many other polypeptides on immunoblots Of a crude microtubule fraction (19” and
observations). Further studies with
antibodies to pure antigens are necessary in order
to establish the nature of the antigen detected by
the “antitubulin antiserum.” Antigenic determinants
unique to ANTS have recently been found in some
Pick bodies as well 128, 1061. It is possible that these
inclusions belong to the type that contains paired helical filaments.
Lewy Bodies
Lewy bodies are round cytoplasmic inclusions characteristic of idiopathic Parkinson’s disease. Lewy bodies
are most prominent in the substantia nigra, but are also
often found in a number of other brainstem nuclei,
especially in aminergic systems, and in the substantia
innominata, where Lewy first described them 127, 34,
80, 81, 91). Like many of the other inclusions discussed in this report, Lewy bodies can be found in
small numbers in the central nervous system of people
who are apparently normal neurologically. Similar inclusions can be found in the Guamanian and familial
forms of amyotrophic lateral sclerosis 135, 60, 138).
Ultrastructural studies in the 1960s and 1970s revealed that Lewy bodies are composed of masses of
filaments 129, 36, 1081. The filaments, which are
Annals of Neurology
Vol 19 No 3
March 1986
Fig 2. (A) Immunocytochemicalreaction of a Lewy body in the
substantia nigra with an antineurofilament antibody. Staining
of axons in the surrounding neuropil is also present. ( x 520.)
(B) Immunocytochemicalreaction of a neocortical Lpwy body with
the same antineurofilament antibody, ( x 520,)
straight and unbranched, measure about 8 nm, a size
that places them within the category of IFs. At the
periphery of the inclusion, the filaments are arranged
radially; in the central zone, the filaments appear more
randomly organized and are admixed with dense
granular and membranous material.
Immunocytochemical studies have shown the presence of N F antigens in Lewy bodies 128, 37, 491 (Fig
2A). In our studies, four different polyclonal antisera
to NFs and two monoclonal antibodies, which recognize the 160 kDa and 200 kDa proteins, bound to
Lewy bodies. An antibody to actin and several antibodies that bind to NFTs did not react. Thus Lewy
bodies share some antigenic determinants with normal
NFs, and, given their appearance, are likely to be composed of NFs. Although Lewy bodies and NJTs can
form in the same neuron [59, 1441, it is likely that the
mechanisms that generate the two abnormalities are
Why Lewy bodies form in the neuronal perikaryon
is not known. A reasonable assumption is that the ex-
port of NFs is interfered with, although the fact that
Lewy bodies do not resemble the NF accumulations in
toxic neuropathies suggests that whatever mechanisms
interfere with the axonal transport of NFs in those
disorders do not apply in Parkinson’s disease.
Intraneuronal inclusions similar to Lewy bodies have
been noted in large numbers in the neocortex and
diencephalon of a few individuals. The clinical histories
of patients with this diffuse type of Lewy body formation characteristically include parkinsonian signs and
symptoms and usually, but not always, dementia 173,
921. The distribution of inclusions differs from patient
to patient, but involves the cerebral cortex, hippocampus, basal ganglia, diencephalon, and brainstem, including the substantia nigra. Although senile plaques
and NFTs can be observed in these brains, they are not
always present, or are present in small numbers. Cortical Lewy bodies react with the same anti-NF antisera
that recognize the nigral inclusions 1491 (Fig 2B). It is
possible that the cortical Lewy bodies are formed by
mechanisms similar to those responsible for the generation of Lewy bodies in the brainstem.
Neurofilament Accumulations
Apparently normal NFs accumulate in neuronal
perikarya and processes in a variety of conditions.
These include amyotrophic lateral sclerosis 118, 581,
animal models of motor neuron disease 1231, and giant
axonal neuropathy 11031. They also include both human and animal neuropathies induced by toxic agents
(as will be discussed). These accumulations are composed of large bundles or swirls of filaments, some
oriented longitudinally along axons (Fig 3A); others
are organized in oblique, interwoven skeins. The
filaments themselves appear ultrastructurally to be normal NFs. Thus, these accumulations are unlike the
tangles made up of PHFs or 15-nm straight filaments,
and are unlike Lewy or Pick bodies. Filament aggregates in amyotrophic lateral sclerosis react with antiNF antibodies (Fig 3B), but not with anti-ANT antibodies 1281. The cause of these abnormalities in motor
neuron disease is not known, although studies of experimental models have shed some light on what may
be common mechanisms.
Giant axonal neuropathy is characterized pathologically by the accumulation of masses of IFs in many
cell types, including neurons 12, 1031. Both the central
nervous system and peripheral nervous system contain
swollen axons filled with NFs. The possibility that this
disease represents a disorder in cytoskeletal system interactions has been raised by the observation that giant
axonal neuropathy fibroblasts in vitro contain juxtanuclear coils of IFs 1971. Similar, if not identical, coils
can be induced in many cultured cells by colchicine, a
drug that depolymerizes microtubules 1101. The loss
of the microtubule system thus has important conse-
Fig 3. (A) Parallelaways of neurofilamentscourse along an axonal spheroid from the spinal anterior horn of a patient with
familial amyotrophic (atera1sclerosis (ALS).{ x 8,000.) (Reprinted from Hirano et al:J Neuropathol Exp Neurol43:471,
1984.) (B) lmmunocytochemical reaction of axonal spheroids in
familial ALS with an antineurofilamentantibody. The section
was counterstained with hematoxylin. ( x 360.)
quences for the organization of IF systems. Furthermore, IF coils induced by colchicine contain MAP2
antigens 1101, suggesting that some of the MAPS serve
to link microtubules with IFs, and will bind to and
distribute with IFs if the microtubule system is impaired.
Masses of 10-nm filaments accumulate in neuropathies resulting from exposure to neurotoxic hexacarbons 183, 111, 131, 1321, carbon disulfide 196,
1281, and acrylamide 178, 1021, and in experimental
disorders induced by aluminum 1145, 1571, IDPN
[2l, 511, or maytansine 1421. The site of accumulation
within neurons differs depending on the chemical, the
dose, and the route of administration. While administration of IDPN or aluminum salts results in proximal
axonal enlargement, other chemicals produce changes
in the distal segment of the axons. The cause of NF
accumulations appears to be related to alterations in
axonal transport and to the dissociation of NFs from
other cytoskeletal proteins, resulting in a physical sep-
Neurological Progress: Goldman and Yen: Neuronal Cytoskeletal Abnormalities 2 15
aration of NFs from other elements. Thus, IDPN and
aluminum impair axonal transport of NFs { 5 , 51, 1701,
but do not affect fast transport or the movement of
tubulin and actin. Ultrastructural studies of IDPNinduced disease have shown a lateral segregation of
organelles within axons, with NFs accumulating in a
subcortical ring surrounding a central channel of microtubules, mitochondria, and smooth endoplasmic reticulum. A similar cytoskeletal segregation can be produced in the peripheral nervous system by hexacarbon
The 10-nm filaments found in neurotoxin-induced
lesions bind NF antibodies {25, 43, 1271, but do not
bind monoclonal anti-ANT antibodies 1281. Furthermore, bundles of filaments isolated from anterior horn
cells of aluminum-treated animals contain proteins
with molecular weights identical to those of normal
NF proteins E1271. It is thus likely that the filamentous
accumulations are made up of NFs. Whether these
NFs have been somehow altered is not known. Aluminum-induced NF accumulations bind monoclonal antibodies that react with phosphorylated epitopes on NFs
[28, 1467. This was an unexpected finding as antibodies that recognize phosphorylated NFs ordinarily
do not bind well to neuronal cell bodies or proximal
axons 11361.
The biochemical basis of the segregation of cytoskeletal elements is uncertain. Direct intermolecular
crosslinking of NFs, or alteration of the physiochemical properties of NF proteins leading to strong NFNF interactions, has been suggested. Toxic agents may
also disrupt normal interactions between NFs and
other cytoskeletal systems, in some way removing NFs
from transport mechanisms. In view of the fact that
NFs and MAPS are highly phosphorylated proteins,
and given the interactions between different cytoskeletal systems described earlier, it is conceivable that
neurotoxic agents may produce cytoskeletal deformation by means of their direct or indirect interference
with protein phosphorylation. Thus, a comparison of
protein phosphorylation under both normal and
neurotoxic or other neuropathological conditions may
reveal some clues concerning the biochemical mechanisms underlying neurofibrillary abnormalities. A recent study of IDPN neuropathy 1951 showed that a
MAP2 antigenic determinant was found with the NFs
at the axonal periphery but not with the microtubules
located at the center of the axons. This observation is
reminiscent of the MAP localization to IF coils after
colchicine treatment 1101 and further indicates an abnormal cytoskeletal segregation.
Contractile Protein Abnormalities
Rod-shaped, eosinophilic inclusions, or Hirano bodies,
represent a cytoskeletal abnormality that is composed
at least in part of actin filaments {46]. These inclusions
216 Annals of Neurology Vol 19 No 3 March 1986
were first described in the brains of patients with
amyotrophic lateral sclerosidParkinson’s disease complex on Guam [551, but have been described in Alzheimer’s and Pick‘s disease, amyotrophic lateral
sclerosis, and kuru, as well as in the brains of
neurologically normal individuals 130, 44, 903. Their
numbers increase with the age of the patient, and they
are particularly prevalent in Alzheimer’s disease 1443.
In the human central nervous system, Hirano bodies
generally show a more restricted distribution than do
NFTs. Most are found in Sommer’s sector of the hippocampus, in the underlying stratum lacunosum, and
in the subiculum. They have also been described in
cortex, cerebellum, and anterior horns. In the hippocampus, Hirano bodies lie primarily in dendrites.
Unlike NFT’s, Hirano bodies are not restricted to
neurons but can be found in glial cells in both the
central and peripheral nervous system {19, 56, 67,
Hirano bodies are composed of a latticework of thin
filaments {57, 118, 1191 (Fig 4). The basic units are
sheets of parallel filaments that cross each other at
oblique angles. The filaments of two adjacent sheets
appear to touch at about 25-nm intervals. Depending
upon the angle of viewing, the inclusions can appear as
cross-hatched lattices, rows of parallel filaments, or
beads on a string. These various appearances can be
observed in the same area of the inclusion if the specimen is tilted in the electron microscope 199, 1431. The
filaments themselves have been reported as measuring
6 to 10 nm. However, thin profiles, the size of
microfilaments, have been noted at the ends of Hirano
bodies and in contiguity with the inclusions 11191.
Application of immunocytochemistry with a variety
of cytoskeletal protein antibodies has revealed the
presence of actin, but not myosin, neurofilament proteins, or tubulin {461. None of the anti-NFT antibodies we have used has reacted with Hirano bodies.
The contention that they are composed of ribosomes
lying on membranes 1891 seems not to have merit in
view of recent immunocytochemical and ultrastructural studies.
There is a murine mutant, brindled (Mob‘), characterized by a deficiency in copper metabolism (641, in
which Hirano bodies are formed during neuronal degeneration {851. Mob‘ Hirano bodies, which are found
in dendrites of Purkinje cells and in neocorrical and
hippocampal neurons, appear structurally identical to
those in human brain. They also react with an antiactin
antiserum at both the light and electronmicroscopic
level 1991. We have observed Hirano body formation
in its early stages, a process characterized by one or
two strands of the lattice surrounded by randomly
oriented thin filaments in a granular matrix within the
dendritic cytoplasm. In some neurons, particularly cortical cells, skeins of filaments are formed without the
Fig 4. Electronmicrograph of an Hirano body in brindled mouse
central nervous system. Two views are present in this micrograph: parallel sheets of filaments (center)and cross-hatched latticework (ends).( x 40,000.)
fully formed latticework. Besides the formation of
Hirano bodies, other important structural changes occur in the dendrites. Microtubules disappear, membrane systems become disorganized, and the dendrites
change shape dramatically. Our current point of view is
that Hirano bodies form in at least two stages. The first
involves rearrangement of the normal F-actin within
the neuron, andor a shift in the G to F actin equilibrium, which promotes polymerization. The second
stage involves the further organization of filaments into
regular latticeworks. Furthermore, whatever alters actin organization also depolymerizes microtubules. The
marked changes in dendritic shape may well be secondary to changes in cytoskeletal protein organization.
Several other neuronal inclusions that to date have
been less carefully scrutinized than those described
above have recently been discovered to contain cytoskeletal elements. Filamentous inclusions of a paracrystalline nature in caudate and nigral neurons contain
actin 1481. The presence of these bodies is of no
known pathological significance 170). Intranuclear
masses of 10-nm filaments are the characteristic cellular change of a rare neurodegenerative disorder [54].
Biochemical and immunocytochemical evidence indicates that these so-called intranuclear hyaline bodies
are NFs {941. How NFs accumulate in nuclei remains
a mystery. Granulovacuolar degeneration is an abnormality present in hippocampal neurons of patients with
Alzheimer’s disease [142]. A recent immunocytochemical study has reported binding of an antitubulin
antibody to granulovacuolar change [1011. This observation is the first to note the presence of tubulin antigen, or antigens, in an abnormal inclusion.
Future Research
Major advances in our understanding of cellular
neuropathology have occurred in the last few years.
Progress has been the result of the rapidly expanding
knowledge of neuronal cytoskeletal proteins and of
recent technical progress, notably the use of specific
polyclonal and monoclonal antibodies as probes for
specific molecular structures. Immunological methods
will continue to be used. For example, the generation
of monoclonal antibodies to specific domains of cytoskeletal proteins will allow a more detailed evaluation
of which specific antigens are present in abnormal inclusions. Care must be taken to define antigenic reactivities and cross-reactivities in interpreting purely
immunocytochemical results. New knowledge of cytoskeletal protein interactions and how posttranslational modifications, such as phosphorylation or proteolysis, may alter such interactions will be important.
Further studies on experimental and hereditary animal
models in which cytoskeletal abnormalities are produced will allow insights into early stages of cytoskeletal disorganization. We also predict that future
biochemical studies will focus on the isolation and di-
Neurological Progress: Goldman and Yen: Neuronal Cytoskeletal Abnormalities 2 17
Cytoskeletal Abnomlities”
Conditions Where Found
Composition (partial)
Neurofibrillary tangles
Alzheimer’s disease
Down’s syndrome
Progressive supranuclear palsy
Postencephalitic Parkinson’s disease
Parkinsoddementia of Guam
Dementia pugilistica
Dystonic lipidoses
Normal aging
Pick‘s disease
PHFs andor straight 10 to 15-nm
filaments; antigens in common with NFs,
MAPS, plus unique antigens
Pick bodies
Lewy bodies
Cortical Lewy bodies
NF accumulations
Intranuclear “hyaline”
Hirano bodies
Rod-shaped inclusions in
caudate and substantia nigra
Granulovacuolar change
Parkinson’s disease
Parkinson’s disease with or without
Amyotrophic lateral sclerosis
Animal models of motor neuron
Toxic neuropathies (e.g., IDPN,
CS2,aluminum, hexacarbons)
lntranuclear hyaline inclusion
Alzheimer’s disease
Amyotrophic lateral sclerosis
Glial cells in axonopathies
Brindled mouse (copper deficiency)
N o known significance
Alzheimer’s disease
Normal aging
10 to 20-nm filaments plus PHFs; react
with NF antibodies
10-nm filaments; react with NF antibodies
10-nm filaments; react with NF antibodies
Latticework of thin filaments; react with
actin antibodies
Paracrystalline, thin filaments; react with
actin antibody
Reacts with tubulin antibody
T h e table gives conditions in which the various abnormalities may be found, but is not meant to be fully inclusive. Compositions are summarized
by giving major ultrastructural features and what is known about biochemical properties and antibody reactivities. The full compositions of the
inclusions and mechanisms of genesis are not yet known.
NF = neurofilament; MAP = microtubule-associated protein; PHF = paired helical filament; IDPN = p-p’-iminodipropionitrile;CS2 =
carbon disulfide.
rect characterization of cytoskeletal inclusions and on
in vitro studies with isolated cytoskeletal proteins to
study directly any possible interactions between toxins
and filament systems and to attempt to generate some
of the abnormalities.
Many of the prominent cellular changes in major
neurodegenerative diseases represent alterations in cytoskeletal proteins (Table).
In conditions such as amyotrophic lateral sclerosis,
certain toxic neuropathies, giant axonal neuropathy,
and Parkinson’s disease, NFs accumulate in cell bodies
or along axons. It is likely that NF proteins are synthesized by neurons, but then are not exported from the
perikarya or transported properly along axons. While
there may be many reasons for these abnormalities, we
might consider two general explanations to account for
common features. The first is that NFs are modified so
218 Annals of Neurology
Vol 19 No 3 March 1986
that they can no longer move into or along axons. Such
modification could include direct cross-linking by toxins, phosphorylation, partial proteolysis, or other posttranslational modifications. The second is that NFs are
not themselves altered but that the interconnections
that associate them with other cytoskeletal systems,
particularly microtubules, are interrupted. Some combination of both ideas is also possible.
In some conditions, such as Alzheimer’s disease, abnormal accumulations of contractile proteins (Hirano
bodies) occur. They may arise from local changes in
dendrites that promote microtubule depolymerization
and shifts in the equilibrium between monomeric and
polymeric actin. Such changes in the dendritic cytoskeleton are accompanied by profound changes in
dendritic size and shape.
In Alzheimer’s disease, Pick‘s disease, progressive
supranuclear palsy, Down’s syndrome, and a variety of
other disorders, filaments accumulate in NFTs that
contain amino acid sequences of NFs and MAPS, but
that also have new properties, not present in normal
cytoskeletal systems. These new properties are likely
to be generated by posttranslational modification of
normal structures, but it is not yet clear how this
None of these abnormalities is itself the underlying
cause of a given neurological disease, but rather a
reflection of the disease. Nevertheless, cytoskeletal abnormalities are well worth studying because understanding how they form will provide important insights
into how neuronal metabolism changes in these conditions. Furthermore, since cytoskeletal elements are
critically involved in maintaining cell shape and in axonal transport processes, the disorganization of a
neuron’s cytoskeleton will in turn have profound consequences on neuronal function.
Supported in part by United States Public Health Service Grants
NS17125, AG05386, AG01136, AG04145, and TeacherInvestigator Award NS00524 (Dr Goldman).
We thank Drs Asao Hirano and Kmuko Suzuki for electron micrographs and Mrs Marilyn Sass0 for secretarial assistance.
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