PATHOPHYSIOLOGY OF PARKINSON’S DISEASE

1 2 3
P A T H O P H Y S I O L O G Y O F
P A R K I N S O N ’ S D I S E A S E
M I C H A E L J . Z I G M O N D
R O B E R T E . B U R K E
Parkinson’s disease (PD) is thought to affect more than 1
gidity, bradykinesia (or slowing of movement), and postural
million people in the United States alone, 1 of every 100
instability. Not all patients initially present with all of the
individuals above the age of 55. In the two centuries since
classic signs of the disorder; there may be only one or two.
it was first described by James Parkinson, we have learned a
Often, the first complaint is one of motor weakness or stiff-
great deal about the disorder. We have, for example, learned
ness, and the cause is commonly misdiagnosed. However,
where the primary lesion is and what many of the clinical
postural deficits and tremor may soon emerge, prompting
manifestations are. However, it has only been in the past
a reconsideration of the basis of the problem. It is important
few decades that insights have begun to emerge regarding
to note, however, that the clinical diagnosis of PD is made
the cause of the disease, and only now can one begin to see
on the basis of a medical history and neurologic examina-
the possibilities of treatments emerging that will provide
tion; there is currently no laboratory test that can definitely
more than temporary symptomatic relief. Beginning with
establish a diagnosis. Even neuroimaging, which can be used
the Nobel Prize–winning work of Arvid Carlsson, which
to obtain an estimate of DA loss (15,128), is imperfect and
pointed to the loss of dopamine (DA) as the principal deficit
in any event is too expensive to be used as a routine diagnos-
in PD and to levodopa as a mode of pharmacotherapy, we
tic tool. As a result, it has been estimated that a significant
have come to understand what fails in this disorder and,
number of individuals diagnosed as having PD fail to show
more recently, how we might correct that failure. Moreover,
the histopathologic hallmarks of the disease upon autopsy
although Parkinson focused entirely on motor symptoms,
(48,70,134).
we have come to realize that the disorder is much more
A tremor at rest is one of the most characteristic features
complex and includes a panoply of psychiatric symptoms
of the disease, occurring in 70% of patients (68). Whereas
as well.
it is not required for diagnosis, the prolonged absence of
The clinical features, course, and treatment of PD are
tremor in the course of a patient’s illness should lead to the
presented in detail in Chapters 122 and 124; thus, for the
careful consideration of other neurologic conditions that
purposes of this review of etiology and pathogenesis, we
can present with signs of parkinsonism, including the multi-
only briefly highlight the more important aspects of these
ple system atrophies, progressive supranuclear palsy, corti-
topics, including those of a psychiatric nature. We then
cobasal ganglionic degeneration, and others (94). Rigidity
describe the pathology before turning to several promising
is a motor sign more often appreciated by the examining
leads with regard to the underlying etiology of the disorder.
physician than the patient; it is detected as a resistance to
passive movement of the limbs. It is often uniform in direc-
tions of flexion and extension (‘‘lead pipe rigidity’’), but
CLINICAL SIGNS AND SYMPTOMS
there may be a superimposed ratcheting (‘‘cogwheel rigid-
Motor Manifestations
ity’’). Bradykinesia refers to a slowness and paucity of move-
ment; examples include loss of facial expression, which may
PD is a chronic, progressive neurologic disease. It presents
be misinterpreted as a loss of affect, and associated move-
with four cardinal motor manifestations: tremor at rest, ri-
ments such as arm swinging when walking. Bradykinesia is
not due to limb rigidity; it can be observed in the absence
of rigidity during treatment. When bradykinesia affects the
Michael J. Zigmond: Departments of Neurology and Psychiatry, Univer-
oropharynx, it can lead to difficulties in swallowing, which
sity of Pittsburgh, Pittsburgh, Pennsylvania.
Robert E. Burke: Department of Neurology, Columbia University, New
in turn may cause aspiration pneumonia, a potentially life-
York, New York.
threatening complication. Of the cardinal motor signs, pos-

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1782
Neuropsychopharmacology: The Fifth Generation of Progress
tural instability is the most potentially dangerous, because
have particular premorbid personality traits (126,129,152).
it can lead to falls with resulting fractures. It is also one of the
For example, some have argued that they tend to follow
manifestations that responds less well to levodopa therapy.
socially approved paths, are more introverted, and have less
Tremor may also be less responsive, even early in the course
addictive personalities (e.g., are less inclined to smoke or
(95).
drink) (158). Support for this hypothesis comes from a
An additional motor feature of PD is the freezing phe-
number of studies, including several involving twins that
nomenon, also referred to as ‘‘motor block’’ (51). In its
are discordant for Parkinson’s disease (65,128). Many of
most typical form, freezing occurs as a sudden inability to
these studies suffer from such problems as small sample
step forward while walking. It may occur at the beginning
size and retrospective analysis. Nonetheless, as noted at the
(‘‘start hesitation’’), at a turn, or just before reaching the
outset of this section, the anatomy of basal ganglia circuitry
destination. It is transient, lasting seconds or minutes, and
is consistent with a broad range of functions, and some of
suddenly abates. Combined with postural instability, it can
these could easily affect personality in subtle ways. Might
be devastating. Freezing does not always improve with levo-
one, posit, for example, a ‘‘rigid PD personality’’ that paral-
dopa, and, in fact, can be made worse.
lels the rigid PD motor capacity? The issue is an important
one, not only for our understanding of PD and of the neuro-
biology of behavior, but also because of the value of develop-
Cognitive and Psychiatric Manifestations
ing diagnostic screens that will permit the detection of PD at
It is increasingly clear that there are many parallel circuits
the earliest possible stage. Such early detection will become
within the basal ganglia, each subserving a different function
increasingly important as neuroprotective strategies emerge.
and each modulated by DA (see Chapter 122). Thus, it is
reasonable to predict that patients will have a wide variety
Other Manifestations
of dysfunctions extending well beyond the classic motor
disabilities associated with the disease. Indeed, patients with
In addition to these neurologic signs and symptoms, PD
Parkinson’s disease appear to be at increased risk for a variety
patients often have disturbing sensory symptoms and pain
of cognitive and psychiatric dysfunctions. Most common is
in affected limbs. Many PD patients also have signs of auto-
dementia and depression. However, hallucinations, delu-
nomic failure, including orthostatic hypertension, constipa-
sions, irritability, apathy, and anxiety also have been re-
tion, urinary hesitancy, and impotence in men (90,107,
ported (1). Here we will comment on the most prevalent
133).
of these symptoms.
Dementia is now recognized as one of the cardinal non-
PATHOLOGY
motor manifestations of PD. It is a major cause of disability,
Neuron Loss
and, unlike the motor manifestations, there currently is no
effective symptomatic treatment. Aarsland and co-workers
A hallmark pathologic feature of PD, and essential for its
(2) identified in dementia in 28% of PD patients. The prev-
pathologic diagnosis, is loss of DA neurons of the substantia
alence depends on age; in a study of PD patients over the
nigra pars compacta (SNpc). At the time of death, even
age of 85by Mayeux et al. (108), 65% were demented.
mildly affected PD patients have lost about 60% of their
PD patients with dementia show a more rapidly progressive
DA neurons, and it is this loss, in addition to possible dys-
course (110), and are more likely to be institutionalized,
function of the remaining neurons, that accounts for the
than nondemented individuals (2).
approximately 80% loss of DA in the corpus striatum. We
Years ago, there was debate about whether depression is
have discussed the basis for the need for extensive loss of DA
a primary manifestation of PD or a reaction to having a
neurons before the emergence of gross neurologic deficits in
chronic neurologic illness. There is now little question that
the previous edition of this series (5) and elsewhere (164,
it is a primary manifestation. Mayeux and colleagues (109a)
165). Briefly, our conception is as follows: As the terminals
have found that 47% of PD patients show evidence of
of DA neurons degenerate, there is a reduction in high-
depression, and some have found an even higher incidence
affinity DA uptake. This, coupled with some inherent re-
(147). Moreover, Aarsland and colleagues (2) report that
dundancy in DA terminals and DA receptors, appears to
major depression is much more common among PD pa-
permit striatal function to continue without disruption or
tients who also have signs of dementia (22%) than those
active compensation during early phases of the neurodegen-
who did not (2%). The depression, however, is not related
erative process. After somewhat larger lesions, the remaining
to the severity of motor signs; indeed, many patients are
DA terminals appear to increase the amount of transmitter
depressed prior to the onset of frank neurologic dysfunction.
synthesized and delivered to the extracellular fluid. This
Moreover, the depression is often greater than that seen in
seems to be due at least in part to a net increase in the
individuals with comparably debilitating motor dysfunction
amount of DA released in response to terminal depolariza-
due to other disorders.
tion, a consequence of the transient disruption of the ho-
It has long been suggested that patients with PD can
meostatic regulatory systems that exist within the affected

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Chapter 123: Pathophysiology of Parkinson’s Disease
1783
systems (164). Once released, a portion of the DA appears
of the nucleus basalis of Meynert, and this may be responsi-
to diffuse out of the synapse and into the extracellular space,
ble, at least in part, in some cases, for dementia (159).
where its actions are prolonged due to the relative absence
of high-affinity DA uptake sites. We hypothesize that these
Lewy Bodies
events permit the SNpc to continue to exert dopaminergic
control over striatal cell function as long as some minimal
Another pathologic hallmark of PD is the Lewy body, an
number of DA terminals remain. However, the increased
eosinophilic inclusion identified within neurons. On histo-
synthesis and release of DA may increase reactive metabo-
logic stains, Lewy bodies have an eosinophilic core, and a
lites formed from DA and thus contribute to the progression
surrounding pale halo. They are usually rounded, although
of the disease (see below).
their shape can be pleiomorphic (50), and they are generally
Neurologic deficits emerge when the availability of DA
5to 25 m in diameter. They usually are observed within
falls below the level required for rapid compensation or
the cell soma, but also can be seen in neurites or free in the
when the system is subjected to certain pharmacologic, envi-
extracellular space. Lewy bodies are commonly observed in
ronmental, or physiologic challenges. These can subside if
the brain regions showing the most neuron loss in PD,
additional, slowly developing compensations, such as the
including SN, locus coeruleus, the dorsal motor nucleus of
synthesis and insertion of additional DA receptors, the in-
the vagus, and the nucleus basalis of Meynert, but they are
duction of typrosine hydroxylase (TH) synthesis, sprouting,
also observed in neocortex, diencephalon, spinal cord, and
or regeneration, occur at a more rapid rate than does the
even peripheral autonomic ganglia (50).
underlying neurodegeneration. This has been observed to
On ultrastructural analyses, Lewy bodies consist of an
be the case in animal models, wherein recovery often occurs
electron dense granular core and a peripheral halo consisting
after the abrupt loss of even 90% of striatal DA, as occurs
of radially oriented filaments 7 to 8 nm in width (28). The
in most animal models. In patients, however, where the
filaments resemble neurofilaments, and can be immuno-
degenerative process is typically progressive, such recovery
stained with antisera to neurofilament proteins (53), includ-
would not be expected to occur spontaneously. However,
ing the NF-L, -M, and -H forms (67). Immunostaining can
an important implication of the ability of brain to compen-
be achieved with antibodies that recognize phosphorylated
sate for partial loss of DA neurons in these ways is that once
as well as nonphosphorylated epitopes (13,40). The cellular
deficits do occur, the task of medicine need not be to restore
kinases responsible for the phosphorylation are not known.
However, two candidates, Ca2 /calmodulin–dependent
the entire nigrostriatal projection but only the far less daunt-
protein kinase II (75) and cyclin-dependent kinase 5 (14,
ing objective of returning the availability of DA to the level
98,118), have both been immunolocalized to Lewy bodies.
required to attain the preclinical state.
Another major antigenic feature of Lewy bodies is the
Although there are several groups of dopaminergic neu-
expression of cellular proteins involved in protein degrada-
rons in the central nervous system (CNS), it is the loss of
tion, including ubiquitin (93), and the proteasome (37,71).
DA cells in the SNpc that is believed to account for all
Presence of these antigens has been hypothesized to repre-
of the motor manifestations of PD. This clinicopathologic
sent efforts on the part of the cell to degrade the abnormal
correlation is supported by observations that the N-methyl-
protein aggregate.
4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is selective
Following the identification of mutations in the
-sy-
for DA neurons of the SNpc in humans and primates, and
nuclein gene in a few cases of familial PD (see below), it
yet can produce the full spectrum of motor signs seen in
was discovered that
-synuclein is a component of Lewy
PD (96). Moreover, it is not even all of the SNpc DA neu-
bodies (11,142,143).
-Synuclein in Lewy bodies can be
rons that appear to be involved in PD. The ventral-lateral
labeled with antibodies to the C- or N-terminal, suggesting
tier is more severely affected than the dorsal tier (36), and
that full-length molecules are present (142).
-Synuclein
this accounts for a more severe loss of DA in the putamen,
immunostaining is identified in isolated Lewy filaments,
where dorsally the loss can be as much as 95%, as compared
and the pattern of staining suggests a polar orientation of
to the caudate, where ventrally the loss can be as little as
the molecules (142). Staining of filaments in situ has been
60% (87). Some central dopaminergic systems, such as the
confirmed by immunoelectron microscopy (10). Synphilin,
ventral tegmental area and hypothalamic systems, are rela-
a protein known to interact with -synuclein (33), also has
tively spared, and descending spinal dopaminergic systems
been identified within Lewy bodies in PD (156).
are spared entirely (6).
-Synuclein is identifiable not only in Lewy bodies of
Although some DA neurons are spared in PD, it is also
PD, but also the Lewy bodies of Hallervorden–Spatz syn-
the case that neuron loss is not restricted to the dopami-
drome (8), familial Alzheimer’s disease (99), sporadic Alz-
nergic neurons. Other catecholaminergic cell groups includ-
heimer’s (55), Alzheimer’s associated with Down syndrome
ing the locus coeruleus are involved, as are some cells of the
(100), and diffuse Lewy body disease (10,11). In Alzhei-
sympathoadrenal system and the serotoninergic neurons of
mer’s disease, Lewy bodies demonstrated by immunostain-
the raphe nuclei (6). There is also loss of cholinergic neurons
ing for -synuclein are most often observed in the amygdala.

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1784
Neuropsychopharmacology: The Fifth Generation of Progress
The demonstrations of Lewy bodies in Alzheimer patients
ber of epidemiologic studies that have been well reviewed
add to the growing evidence of important pathologic over-
by others (97,148). Many of these studies have shown asso-
laps between Alzheimer’s and PD. This evidence is further
ciations between rural residence, well-water drinking, or
supported by the demonstration of co-localization of phos-
herbicide/pesticide exposure and the risk of developing PD
phorylated
and
-synuclein in Lewy bodies of PD and
(148). However, the precise role played by any specific com-
diffuse Lewy body disease (9).
pounds has remained elusive.
In addition to its localization in Lewy bodies in PD,
abnormal -synuclein immunostaining has been identified
Genetic Factors
in axon terminals in the hippocampal dentate, hilar, and
CA 2/3 regions in PD (44). Whereas immunostaining for
For many years, genetic factors were considered unlikely to
-synuclein has not been observed in Lewy bodies, staining
play an important role in the pathogenesis of PD. This
was observed in these axon terminals. In addition, although
concept was based largely on twin studies conducted in the
immunostaining for -synuclein is not present in Lewy bod-
early 1980s that demonstrated a very low rate of concor-
ies, it is observed within axonal spheroids in the hippocam-
dance for the disease among identical twins (157) [reviewed
pal dentate molecular layer in PD (44).
by Duvoisin (29)]. Nevertheless, many investigators recog-
nized that PD could occasionally be identified in families
(52). The most important advances in PD research in recent
ETIOLOGIC FACTORS
years have been the identification of specific disease-causing
mutations, making it possible for the first time to begin to
Aging
explore pathogenesis at the molecular level. For this review,
The possible role of aging in the pathogenesis of PD is
we focus on the best documented and most widely investi-
suggested by its usual occurrence in late middle age, and
gated genetic causes—those in -synuclein and parkin.
by marked increases in its prevalence at older ages (109).
The possible contribution of age to the expression of the
Synuclein
disease is further supported by early studies showing a loss
with age of striatal DA (18) and DA of cells in the SN (113).
After mapping a disease-causing gene locus to the 4q21-
However, whereas the gradual loss of striatal dopaminergic
q23 region (130) in a large Italian kindred (52), Polymero-
markers (88,138) and SNpc neurons (36) with age has re-
poulos and co-workers (131) identified a base pair change
cently been confirmed, the pattern and timing of these losses
from G to A at position 209, which resulted in an Ala to
differ from what occurs in PD, indicating that aging itself
Thr substitution at position 53 in -synuclein in this family
is not likely to play a direct role in the degenerative process.
and three small Greek kindreds. Whereas initially there was
For example, although the number of dopaminergic termi-
a question as to whether this may represent a benign poly-
nals appears to decrease with age, this takes place with a
morphism, that possibility was soon dispelled by the discov-
different temporal and spatial pattern than occurs in PD
ery of a second disease-causing mutation, an Ala to Pro
(138). The loss of SN neurons in aging is linear and predom-
substitution at position 30, in an unrelated German kindred
inantly in the dorsal tier of the SNpc, whereas in PD it is
(92). The likely role of -synuclein in the pathogenesis of
exponential and predominantly in the lateral ventral tier
PD was further supported by the discovery of synuclein
(36,138). In addition, the SN in PD contains numerous
in Lewy bodies of sporadic PD cases, as outlined above.
reactive microglia, which are much less frequent in age-
One of the important aspects of the discovery of these muta-
matched control brains, indicating an active destructive pro-
tions in -synuclein was that they immediately suggested a
cess that is not present in the normal aged brain (111,112).
possible pathogenetic mechanism, that of protein aggrega-
Thus, whereas there is no question that increased age is a
tion, because -synuclein had been identified in Alzheimer
risk factor for PD, it remains unclear what precise role aging
plaques (154), and a central portion of
-synuclein had
plays in pathogenesis.
been shown to have the capacity to self-aggregate (56). The
role of
-synuclein in the protein aggregation hypothesis
for PD is discussed in the next section.
Environmental Factors
Little is known about the normal physiologic function
Consideration of a role for environmental factors in the
of -synuclein. Scheller’s group (104) was the first to dis-
cause of PD was given major impetus with the discovery
cover the compound, identifying it in Torpedo as a brain-
in 1983 that exposure to MPTP is capable of inducing par-
specific synaptic terminal protein. These investigators sub-
kinsonism in humans (96). The role of environmental fac-
sequently demonstrated that the rat protein homologue is
tors was given additional weight by initial results of twin
likewise expressed in nerve terminals (105).
-Synuclein
studies, as discussed below, which initially appeared to ex-
messenger RNA (mRNA) is predominantly expressed in
clude any important role for genetic factors. The possible
forebrain structures, such as hippocampus and cortex, but
role of environmental factors has been addressed by a num-
also in a few specific midbrain-brainstem nuclei, including

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Chapter 123: Pathophysiology of Parkinson’s Disease
1785
the SNpc, locus coeruleus, and dorsal motor nucleus (105),
large Greek family with the G209A mutation that there is
which, interestingly, are typically involved in PD. The
diminished expression of the mutant allele in lymphoblas-
human homologue of -synuclein was independently iden-
toid cell lines, and they suggest that the parkinsonian pheno-
tified by Ueda et al. (154) and Jakes et al. (78), and demon-
type may arise from haploinsufficiency.
strated by Irizarry and colleagues (76) to be expressed in
nerve terminals, as is the case for rat. These investigators also
showed by fractionation studies that -synuclein appears to
Parkin
be loosely associated with synaptic vesicles, and this localiza-
tion has been confirmed in rat brain by ultrastructural analy-
Mutations in the parkin gene were first identified in Japa-
sis (74). Jensen and his colleagues (82) have shown that -
nese families with a unique variant of parkinsonism (89).
synuclein binds to vesicles via its amino-terminal region,
This form is inherited in an autosomal-recessive pattern,
and that it is carried with vesicles by the fast component
and typically begins at an early age; in the series of 17 pa-
of axonal transport. Interestingly, the A30P mutation ap-
tients studied by Ishikawa and Tsuji (72), the age ranged
pears to abolish vesicle-binding activity.
from 9 to 43 years, with a mean of 28. Many of the clinical
What specific physiologic role -synuclein and its homo-
features of patients with autosomal-recessive juvenile par-
logues may play as vesicle-binding proteins remains a mys-
kinsonism (ARJP) closely resemble those of idiopathic PD:
tery. George and co-investigators (46) independently identi-
tremor at rest, rigidity, bradykinesia, postural instability,
fied an avian homologue of -synuclein, synelfin, as a gene
gait freezing, and marked improvement with levodopa.
upregulated in the song control circuit during a critical pe-
However, there are differences between ARJP and idio-
riod of song learning, and suggested that it plays a role
pathic PD in addition to the age at onset. Patients with
in neural plasticity (46). We have shown that -synuclein
ARJP more often present with dystonia, show a marked
mRNA and protein are upregulated in the SNpc following
clinical improvement after sleep, and often show hyperre-
early developmental striatal target lesion (85). This lesion
flexia (72). In general, they do not show cognitive decline
results in the induction of apoptotic death in some, but not
or autonomic failure, and the course is slowly progressive.
all, developing dopaminergic neurons (102). However, in
The motor predominance of their clinical signs is in keeping
this model -synuclein is not expressed in apoptotic pro-
with the pathologic findings, which indicate neuronal loss
files; it is exclusively upregulated in normal-appearing neu-
restricted to neurons of the SNpc and the locus coeruleus
rons, suggesting that it plays a role either in maintaining
(146). Lewy bodies are not observed (146).
their viability, or, alternatively, in plastic change after viabil-
ARJP was found to map to the chromosome 6q25.2-27
ity is established. Vila and co-workers (155) reached a simi-
region, and a marker for this region, D6S305, was found
lar conclusion in a model of chronic MPTP toxicity. In
to be deleted in a single Japanese patient (89). Screening
support of the possibility that -synuclein may play a role
of complementary DNA (cDNA) libraries with a probe for
in a plasticity response in these injury models is the observa-
a putative exon, which was also deleted in this patient, led
tion that -synuclein mRNA in SN is up-regulated during
to the identification of a sequence encoding an open reading
the first 4 postnatal weeks, a period of maximal differentia-
frame for a 465amino acid protein (89). The deduced
tion and synaptogenesis among DA neurons (85). What
amino acid sequence of this protein contains a ubiquitin
precise role
-synuclein plays in the development of DA
homology domain at the N-terminal, and a ring-finger
neurons remains to be established. Remarkably, homozy-
motif at the C-terminal. The gene encoding the protein is
gous -synuclein null mice have thus far shown no obvious
large [ 500 kilobase (kb)], and contains 12 exons. Deletion
abnormalities in numbers or morphology of DA neurons;
mutations were identified in four other affected patients
density of striatal dopaminergic terminals; the number,
in three independent families, confirming the pathogenetic
morphology, or patch/matrix distribution of striatal neu-
significance. A 4.5-kb mRNA transcript was identified in
rons; or the ultrastructural appearance of striatal synaptic
many human tissues, including brain. In brain, it is ex-
terminals (4). These animals, however, do exhibit an in-
pressed in various regions, including the SN (89).
creased release of DA in a paired stimulus depression para-
Subsequent molecular genetic analysis of 34 affected in-
digm. In addition, they show diminished behavioral activa-
dividuals from 18 unrelated Japanese families revealed four
tion following administration of amphetamine (4).
additional deletional mutations (64), bringing the total to
In view of
-synuclein’s ability to self-aggregate, there
six identified at that time (89). The deletions affected exon
has been a tendency to assume that the mutations cause a
3, exon 4, and exons 3 to 4, and a 1–base pair (bp) deletion
toxic gain of function related to aggregation. It is important
in exon 5resulted in a frameshift and an early stop. Further
to keep in mind, however, that its function is unknown, and
molecular analysis of non-Japanese families in Europe, re-
that a loss of function may relate to disease pathogenesis. In
vealed that in addition to deletion mutations, a variety of
that regard, we have found that -synuclein mRNA levels
point mutations resulting in either truncation or missense
are diminished in the SNpc of patients with sporadic PD
could also cause the phenotype (3). In addition, this study
(120). Markopoulou and colleagues (103) have shown in a
identified patients with a late age of onset, up to 58 years

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1786
Neuropsychopharmacology: The Fifth Generation of Progress
in one case, and indicated that in some instances the clinical
auto-oxidation of DA. This auto-oxidation generates toxic
phenotype was indistinguishable from idiopathic PD (3).
quinones and reactive oxygen species. In addition, the pres-
There is now growing recognition that mutations in par-
ence of neuromelanin in the cell may alter the ability of
kin may cause what clinically resembles idiopathic PD. In
metal ions to participate in the production of reactive oxy-
an investigation of the scope of the molecular and clinical
gen species (145).
features in Europe, Lucking and co-workers (101) found
The possibility that DA neurons may undergo free radi-
that among 73 families with early onset ( 45years) of
cal–mediated injury in PD has received support from ani-
parkinsonism and affected family members, 49% had par-
mal studies using one of two neurotoxins that can be used to
kin mutations. Among early-onset patients without affected
selectively destroy DA neurons—6-hydroxydopamine (6-
family members, 18% had mutations. The majority (77%)
OHDA) and MPTP. 6-OHDA reacts with oxygen to pro-
of these were younger than 20 years of age. Many of the
duce superoxide anion radical, H2O2, and hydroxyl radical.
patients with parkin mutations lacked the signs thought to
It is a general cytotoxin but derives its specificity by virtue of
be characteristic of ARJP such as dystonia and hyperreflexia,
its affinity for the high-affinity catecholamine transporters.
and were clinically difficult to distinguish from idiopathic
Thus, when used in sufficiently low concentrations, its ac-
PD. In all, 19 different rearrangements of exons mutations
tions can be directed toward catecholamine neurons. More-
were identified, including multiplications as well as dele-
over, it can be limited to acting on DA neurons by pre-
tions, and there were 16 different point mutations (101).
treating animals with an inhibitor of high-affinity
The neurobiology of parkin is only beginning to be ex-
norepinephrine uptake, such as desipramine (19,66,166).
plored. By immunohistochemistry, the protein has been lo-
Interestingly, like 6-OHDA, DA itself is a selective neu-
calized at the regional level to SN and locus coeruleus, and
rotoxin for DA neurons (38,54,61,62,114,135). This seems
at the cellular level to the cytoplasm (139). Nuclear staining
to be in large part due to its ability to oxidize to form
was not observed. Parkin has been shown to play a role in
reactive oxygen species, including DA quinone, which has
protein degradation as a ubiquitin-protein ligase (140).
a high affinity for the cysteinyl residues on proteins (41–43,
These findings suggest that abnormal accumulation of pro-
54,63). Thus, it seems possible that DA itself can be a source
teins or abnormal regulation of the half-life of normal cellu-
of oxidative stress, particularly under conditions of increased
lar proteins may play a role in cell death.
DA turnover and decreased antioxidant defenses (see
below).
MPTP acts via its active product MPP , which is selec-
PATHOGENETIC MECHANISMS
tively taken up into DA neurons via the DA transporter,
Free Radicals and Deficits in Energy
and inhibits complex I activity in mitochondria. Inhibition
of complex I not only interferes with adenosine triphosphate
Metabolism
(ATP) synthesis, but also results in augmented production
The concept that free radical–mediated injury may underlie
of superoxide anion radical. The possible role of superoxide
the neuronal degeneration that occurs in PD has been, and
radical in MPTP toxicity has received direct support by the
continues to be, the leading hypothesis for its pathogenesis.
demonstration by Przedborski and co-workers (132) that
The free radical theory has been the subject of many excel-
transgenic mice with high Cu/Zn superoxide dismutase ac-
lent reviews (34,122), so it will be outlined here only briefly.
tivity are resistant to MPTP.
This theory is also referred to as the oxidant stress hypothesis
The free radical hypothesis of PD has also received sup-
or the endogenous toxin hypothesis. In their review, Fahn
port from studies of human postmortem brain. Free radicals
and Cohen (34) point out that the free radical hypothesis
can cause injury to cells by damaging DNA, proteins, and
is appealing because four aspects of the neurochemistry of
lipids of the cell membrane. There is evidence from post-
DA neurons and their local environment within the SN
mortem studies for free radical–induced modification of
make the concept plausible. First, a major degradative path-
each of these classes of molecules. Dexter and co-workers
way for DA is its oxidative deamination by monoamine
(24) have shown that in PD brain there is a reduction in
oxidases A and B. This process results in the enzymatic
levels of polyunsaturated fatty acids, which provide an index
production of H2O2, which, while itself not a free radical,
of the amount of substrate available for lipid peroxidation,
can nevertheless react nonenzymatically with ferrous or cu-
and an increase in levels of malondialdehyde, an intermedi-
pric ions via Fenton-type reactions to form highly reactive
ate in the lipid peroxidation process. The increase in malon-
hydroxyl radicals. Second, DA can react nonenzymatically
dialdehyde was regionally specific for the SN. These workers
with oxygen to form quinones and semiquinones, with the
subsequently confirmed evidence for abnormal lipid peroxi-
production of superoxide, hydrogen peroxide, and hydroxyl
dation in PD by identifying a tenfold increase in cholesterol
radicals. Third, the SN, particularly the SN pars reticulata,
lipid hydroperoxide, an early marker in the lipid peroxida-
is rich in iron, which as mentioned above, may in its ferrous
tion process (25). Free radicals are also capable of directly
state catalyze the formation of hydroxyl radicals from H2O2.
damaging DNA. Sanchez-Ramos and colleagues (136) have
Fourth, the SN contains neuromelanin formed from the
shown that regional concentrations of 8-hydroxy-deoxygua-

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Chapter 123: Pathophysiology of Parkinson’s Disease
1787
nosine, an index of oxyradical-mediated DNA damage, are
cific for the SN, and disease specific, among basal ganglia
increased in the caudate and SN of PD patients. Relatively
disorders, for PD.
less attention has been given to the possibilities of oxygen-
Thus, the free radical hypothesis receives indirect support
mediated damage to proteins, or of advanced glycosylation
from a large number of separate lines of evidence, and, as
changes to proteins in PD (141). The possibility that such
stated above, it remains the foremost and most widely tested
protein changes may also occur in PD brain is supported
hypothesis of neural degeneration in PD. Nevertheless, it
by the demonstration that protein adducts of 4-hydroxy-2-
remains only a hypothesis, and it has its shortcomings (17).
nonenal, a cytotoxic product of lipid peroxidation, can be
For example, there is no specific aspect of the free radical
identified by immunohistochemistry in many nigral neu-
hypothesis as it is currently posed to account for the relative
rons of PD patients in contrast to age-matched controls
vulnerability of ventral tier dopaminergic neurons in PD.
(162).
In addition, it must be remembered that nonaminergic neu-
Postmortem studies have also revealed neurochemical
ronal groups, such as the nucleus basalis, which is choliner-
features that may predispose the PD brain to oxidative dam-
gic, also degenerate in PD, and aspects of the free radical
age. Reduced glutathione is an important endogenous anti-
hypothesis that are dependent on catecholamine metabo-
oxidant, and it has been reported to be reduced in the SN
lism are not relevant to the degeneration of these structures.
in PD (127). Jenner and colleagues (80) have confirmed
low levels of reduced glutathione in the SN of PD patients,
Programmed Cell Death
and have shown that the alteration is disease-specific. Inter-
estingly, they have also shown that reductions are observed
The concept that a genetically regulated cell death process
in patients with incidental Lewy body disease, which may
may underlie the neuron-specific degenerations of later life
be a preclinical form of PD (49). This finding suggests that
has gathered great attention in recent years. The pro-
the reduced levels of glutathione may be a fundamental and
grammed cell death hypothesis in fact may be related to
primary abnormality in PD, rather than a secondary change.
the concept of free radical–mediated cell death. Although
A number of postmortem studies have also suggested
traditional concepts of free radical injury have centered on
that abnormalities of iron metabolism may underlie the neu-
the ability of toxic molecules to directly injure cellular con-
rodegeneration of PD. Iron metabolism is of particular in-
stituents without any participation of the host cell’s own
terest in relation to the free radical hypothesis because, as
genetic programs, it is now clear that in both in vitro and in
noted above, it normally is found in high concentrations
vivo paradigms of free radical–mediated injury programmed
in SN, and is capable of catalyzing free radical formation.
cell death may occur. It is also apparent that in some settings
Dexter and colleagues (26) reported increased levels of iron
programmed cell death may be carried out by the controlled
in the SNpc of PD patients. This observation took on po-
production of free radicals.
tentially greater significance when this group subsequently
In relation to PD, it is important first to consider the
reported decreased levels of ferritin in PD brains (23), as
evidence that programmed cell death does in fact occur
ferritin normally sequesters iron in an unreactive state.
within dopaminergic neurons. As predicted by classic neu-
However, it has become apparent that increased iron levels
rotrophic theory, some natural cell event does occur during
may be observed in many brain regions demonstrating neu-
development in the SNpc, with typical light microscopic
ral degeneration in a variety of diseases of the basal ganglia
morphology of apoptosis, demonstrated both by Nissl stain
(22), so the specificity of changes in iron levels in PD is
and suppressed silver staining (79), and we used a double-
less clear. Nevertheless, the possible relationship of altered
labeling technique to identify apoptotic natural cell death
iron metabolism to the pathogenesis of PD remains of inter-
in phenotypically defined dopaminergic neurons (123).
est, based on the finding of a higher density of lactoferrin
Natural cell death in these neurons has a bimodal time
receptors on neurons and microvessels of patients with PD
course. There is an initial, major peak that begins on embry-
(35). This finding suggests that lactoferrin receptors, which
onic day 20, and largely abates by the eighth postnatal day
regulate intraneuron iron content, may be overly expressed
(PND). There is a second, minor peak of natural cell death
in vulnerable dopaminergic neurons in PD.
on PND 14. The presence of a postnatal cell death event
Another postmortem finding in PD patients that is com-
is in keeping with the demonstration by Tepper and col-
patible with the free radical hypothesis is that of a deficiency
leagues (151) that there is a decrement in the number of
in mitochondrial complex I. Such a defect could either result
TH-positive neurons in SN postnatally, particularly in the
in the abnormal production of free radicals, or be the result
first postnatal week. Although there is evidence that the
of free radical injury (137). This defect takes on particular
magnitude of the natural cell death event in DA neurons
interest in light of the observation that MPP , the toxic
is regulated by interactions with the target striatum (see
oxidative product of MPTP, inhibits complex I (121). The
below), as classic neurotrophic theory would predict, it re-
defect in complex I in PD patients has been demonstrated
mains unknown which neurotrophic factors are involved.
by Schapira et al. (137) to result in a mean 37% decrease
We have shown in vitro in postnatal primary cultures of DA
in activity. This decrease appears to be both regionally spe-
neurons that GDNF is uniquely able to support viability by

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1788
Neuropsychopharmacology: The Fifth Generation of Progress
suppressing spontaneous apoptotic death (16) as well as cell
but they were not clearly characteristic of apoptosis.
death initiated by 6-OHDA (see below). Whether glial cell
TUNEL labeling (45) has been demonstrated in PD brains
line-derived neurotrophic factor (GDNF) plays such a role
(115). However, the terminal deoxynucleotidyl transferase
in vivo remains to be determined.
dUTP nick end labeling (TUNEL) technique is not entirely
We have shown that natural cell death in SNpc can be
specific for apoptosis since it can also label free 3′-ends that
regulated during development by striatal target interactions.
are generated by necrotic death, producing false positives.
Excitotoxic injury to the striatum on PND 7 results in an
Thus, it is essential to co-identify not only TUNEL labeling
eightfold increase in the number of apoptotic profiles (102).
but also the classic chromatin clump morphology of
These profiles are morphologically identical to those ob-
apoptosis. Tompkins and co-workers (153) and Tatton and
served during natural cell death, and meet ultrastructural
colleagues (150) have both achieved this more specific dem-
and 3′ end-labeling criteria for apoptosis. Within SNpc,
onstration. However, many other investigators have been
induction of cell death is identified within phenotypically
unable to identify specific TUNEL labeling in PD brains
defined dopaminergic neurons.
(12,86,91,160). Thus, a consensus has not been achieved,
Programmed cell death also occurs in DA neurons in
and further investigation will require methods beyond these
animal models of parkinsonism. Intrastriatal injection of 6-
morphologic techniques, such as the utilization of specific
OHDA results in an induction of apoptotic death in pheno-
biochemical markers for programmed cell death. Hartmann
typically defined DA neurons of the SN (106). This induc-
and colleagues (58) have made such an effort utilizing an
tion is most pronounced in a developmental setting,
antibody that is specific for the activated form of caspase-
through PND 14, but it can also be demonstrated, at a
3. They have shown that activated caspase-3 could be identi-
lower level, in mature animals. Interestingly, at older ages
fied in Lewy body–containing neurons of the SN in PD
the morphology of cell death becomes mixed, including
brains (58). However, activated caspase-3 was also identified
apoptotic and nonapoptotic features (106). Although in this
in control brains, in larger numbers of neurons. They attrib-
model 6-OHDA may lead to apoptotic death simply by the
ute this staining to agonal changes. Thus, the staining was
destruction of terminals and the resulting failure of target
not specific for PD, and more study is needed with addi-
support, there is evidence that the toxin also directly me-
tional specific immunoreagents for other components and
diates death. In addition to the fact that 6-OHDA is able
by-products of programmed cell death pathways.
to induce death long after it is possible to demonstrate target
dependence (84), the morphologic features of activated cas-
Protein Aggregation
pase-3 expression, an important mediator of programmed
cell death, differs in 6-OHDA–induced death, as compared
The possibility that protein aggregation may play a role in
to natural and target injury-induced cell death (83).
PD had long been suggested by the presence of Lewy bodies
Other important animal models of parkinsonism, in ro-
in disease brains. However, this concept was given powerful
dents and primates, are induced by MPTP, or its active
support upon discovery of the mutations in
-synuclein.
oxidized product, MPP . A number of investigators have
Human -synuclein was originally identified as a proteoly-
shown in a variety of systems that MPP
can induce
tic fragment derived from Alzheimer senile plaques (154).
apoptosis in vitro. Dipasquale and colleagues (27) first
The isolated fragment, termed the non-A component of
showed that MPP
can induce apoptotic morphology and
amyloid (or NAC), corresponded to a 35amino acid hydro-
DNA fragmentation in postnatal cerebellar granule cells in
phobic portion of
-synuclein. Soon after its discovery,
culture. Subsequently, others have shown that MPP
ap-
NAC was predicted to form
-sheet secondary structure,
pears to induce apoptosis in embryonic mesencephalon cul-
and shown to self-aggregate to form fibrillar amyloid in
ture (116), in PC12 cells, both differentiated (117) and
vitro (56). Thus, with the discovery of -synuclein, PD was
undifferentiated (57), and in a human neuroblastoma cell
placed firmly among neurodegenerative disorders for which
line (73). Tatton and Kish (149) have shown that when
protein aggregation is believed to play an important patho-
MPTP is administered to mice in low doses over a 5-day
genetic role, including Alzheimer’s, motor neuron disease,
course, it induces apoptotic death. In this model, induction
the triplet repeat diseases, and the prion diseases.
of apoptosis is dependent on the dosing regimen; acute ad-
Subsequent biochemical studies have shown that full-
ministration of multiple doses in a single day results in non-
length -synuclein is capable of binding to A 1-38 and
apoptotic death (77). Further support for the role of pro-
forming amyloid (163). This binding requires the hydro-
grammed cell death in the MPTP mouse model derives
phobic NAC region. Other investigators have confirmed -
from the observation that Bax, a mediator of apoptosis, is
synuclein binding to A , and have shown that -synuclein
induced (60). In addition, overexpression of Bcl-2, a protein
is capable of homodimerization (81,124). Even in the ab-
inhibitor of apoptosis, diminishes MPTP-induced injury
sence of A , full-length recombinant -synuclein is capable
(161).
of self-aggregation in vitro to form fibrillar amyloid material
It remains controversial whether apoptosis can be identi-
(59). A number of investigators have confirmed this obser-
fied in the Parkinson brain. One initial report demonstrated
vation, and have found that one or both mutant forms are
intranuclear chromatin clumps by electron microscopy (7),
more likely to form -sheet and aggregate, forming fibrils

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Chapter 123: Pathophysiology of Parkinson’s Disease
1789
that resemble those of Lewy bodies (20,32,47,119).
8. Arawaka S, Saito Y, Murayama S, et al. Lewy body in neurode-
Crowther and co-workers (21) have shown that C-termi-
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filaments that resemble those isolated from diseased brain.
of phosphorylated tau- and NACP/alpha-synuclein-epitopes in
Further analysis of the NAC fragment has shown that
lewy bodies in sporadic Parkinson’s disease and in dementia
the N-terminal sequence is responsible for aggregation (30).
with Lewy bodies. Brain Res 1999;843:53–61.
NAC aggregates have been demonstrated to have cellular
10. Arima K, Ueda K, Sunohara N, et al. Immunoelectron-micro-
scopic demonstration of NACP/alpha-synuclein-epitopes on the
toxicity. They induce apoptotic death in cultured human
filamentous component of Lewy bodies in Parkinson’s disease
neuroblastoma cells (31). Low concentrations of aggregated
and in dementia with Lewy bodies. Brain Res 1998;808:93–100.
NAC are toxic to DA neurons in primary culture and neu-
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of NAC aggregates induced death of SN DA neurons. Based
with Lewy bodies. Am J Pathol 1998;152:879–884.
12. Banati RB, Daniel SE, Blunt SB. Glial pathology but absence
on these demonstrations of the ability of -synuclein and
of apoptotic nigral neurons in long-standing Parkinson’s disease.
NAC to aggregate and the possible toxicity of aggregates,
Mov Disord 1998;13:221–227.
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