_____

The New England Journal of Medicine -- May 17, 2001 -- Vol. 344, No. 20
SPECIAL ARTICLE

Shattuck Lecture -- Neurodegenerative Diseases and Prions

Stanley B. Prusiner

  _____

Twenty-five years ago, little was known about the causes of
neurodegenerative diseases. Now, however, it is clear that they result from
abnormalities in the processing of proteins. In each of these diseases,
defective processing causes the accumulation of one or more specific
neuronal proteins.
Of all the laboratory research on neurodegenerative diseases, the studies
that led to the discovery of prions have yielded the most unexpected
findings. The idea that a protein can act as an infectious pathogen and
cause degeneration of the central nervous system was accepted only after a
long and arduous battle. ( 1
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-1> ) The
concept of prions not only has provided an explanation of how a disease can
be both infectious and genetic, but has also revealed hitherto unknown kinds
of neurologic diseases. This review presents a unifying concept of
degenerative brain diseases, based on what we have learned about prions. ( 2
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-2> )
Alzheimer's disease is the most common neurodegenerative disorder ( Table 1
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=T1> ). In
the United States, approximately 4 million people have Alzheimer's disease,
and approximately 1 million have Parkinson's disease. ( 3
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-3> , 4
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-4> , 5
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-5> ) Much less
common are amyotrophic lateral sclerosis, frontotemporal dementia, prion
diseases, Huntington's disease, and spinocerebellar ataxias.
With the increase in life expectancy, there has been concern about the
incidence of Alzheimer's and Parkinson's diseases. Among persons who are 60
years old, the prevalence of Alzheimer's disease is approximately 1 in
10,000, but among those who are 85 years old, it is greater than 1 in 3. ( 6
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-6> ) These
data suggest that by 2025, there will be more than 10 million cases of
Alzheimer's disease in the United States, and by 2050, the number will
approach 20 million. ( 4
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-4> ) The
annual cost associated with Alzheimer's disease in the United States is
estimated at $200 billion. Age is also the most important risk factor for
Parkinson's disease. Nearly 50 percent of persons who are 85 years old also
have at least one symptom or sign of parkinsonism. ( 7
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-7> )
Virtually all neurodegenerative disorders involve abnormal processing of
neuronal proteins. The aberrant mechanism can entail a misfolding of
proteins, altered post-translational modification of newly synthesized
proteins, abnormal proteolytic cleavage, anomalous gene splicing, improper
expression, or diminished clearance of degraded protein. Misprocessed
proteins often accumulate because the cellular mechanisms for removing them
are ineffective. The particular protein that is improperly processed
determines the malfunction of distinct sets of neurons and thus the clinical
manifestations of the disease.

Prions

Prions are infectious proteins. In mammals, prions reproduce by recruiting
normal cellular prion protein (PrPC) and stimulating its conversion to the
disease-causing (scrapie) isoform (PrPSc). A major feature that
distinguishes prions from viruses is that PrPSc is encoded by a chromosomal
gene. ( 8 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-8> )
Limited proteolysis of PrPSc produces a smaller, protease-resistant molecule
of approximately 142 amino acids, designated PrP 27-30, which polymerizes
into amyloid. ( 9
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-9> )
The polypeptide chains of PrPC and PrPSc are identical in composition but
differ in their three-dimensional, folded structures (conformations). PrPC
is rich in (alpha)-helixes (spiral-like formations of amino acids) and has
little (beta)-sheet (flattened strands of amino acids), whereas PrPSc is
less rich in (alpha)-helixes and has much more (beta)-sheet. ( 10
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-10> ) There is
evidence that PrPC has three (alpha)-helixes and two short (beta)-strands;
in contrast, a plausible model suggests that PrPSc may have only two
(alpha)-helixes and more (beta)-strands ( Figure 1
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=F1> ).
 11 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-11> , 12
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-12> ) This
structural transition from (alpha)-helixes to (beta)-sheet in PrP is the
fundamental event underlying prion diseases.
Four new concepts have emerged from studies of prions. First, prions are the
only known example of infectious pathogens that are devoid of nucleic acid.
All other infectious agents possess genomes composed of either RNA or DNA
that direct the synthesis of their progeny. Second, prion diseases may be
manifested as infectious, genetic, or sporadic disorders. No other group of
illnesses with a single cause has such a wide spectrum of clinical
manifestations. Third, prion diseases result from the accumulation of PrPSc,
which has a substantially different conformation from that of its precursor,
PrPC. Fourth, PrPSc can have a variety of conformations, each of which seems
to be associated with a specific disease. How a particular conformation of
PrPSc is imparted to PrPC during replication in order to produce a nascent
PrPSc with the same conformation is unknown. The factors that determine the
site in the central nervous system where a particular PrPSc is deposited are
also not known.

Prion Diseases

Prion diseases have a broad spectrum of clinical manifestations, including
dementia, ataxia, insomnia, paraplegia, paresthesias, and deviant behavior.
( 13 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-13> )
Neuropathological findings range from an absence of atrophy to widespread
atrophy, from minimal to widespread neuronal loss, from sparse to widespread
vacuolation or spongiform changes, from mild to severe reactive astrocytic
gliosis, and from an absence of PrP amyloid plaques to an abundance of
plaques. ( 14
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-14> ) None of
these findings except the presence of PrP amyloid plaques is unequivocally
diagnostic of a prion disease.
The sporadic form of Creutzfeldt-Jakob disease, which is typically
manifested as dementia and myoclonus, accounts for approximately 85 percent
of all cases of prion disease in humans, whereas infectious and inherited
prion diseases account for the rest. Familial Creutzfeldt-Jakob disease,
Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia are all
dominantly inherited prion diseases caused by mutations in the prion protein
gene (PRNP) ( Table 2
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=T2> ).
 15 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-15> , 16
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-16> , 17
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-17> , 18
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-18> , 19
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-19> )
Experiments that showed transmission of these diseases by filtrates of brain
from familial cases ( 20
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-20> , 21
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-21> ) were
wrongly attributed to a virus. There is no Creutzfeldt-Jakob disease virus,
and familial prion diseases are caused by mutations in PRNP. ( 22
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-22> )
Epidemiologic Features
Prions cause Creutzfeldt-Jakob disease in humans throughout the world. The
incidence of sporadic Creutzfeldt-Jakob disease is approximately 1 case per
1 million population, ( 23
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-23> ) but
among persons between the ages of 60 and 74 years, the incidence is nearly 5
per 1 million. ( 24
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-24> ) Cases in
patients as young as 17 years and as old as 83 have been recorded. ( 23
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-23> , 25
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-25> )
Creutzfeldt-Jakob disease is relentlessly progressive and usually causes
death within a year after its onset. Each geographic cluster of cases of
prion disease was initially thought to be a manifestation of viral
communicability, ( 26
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-26> ) but each
was later shown to be due to a PRNP gene mutation except for new variant
Creutzfeldt-Jakob disease.
Neuropathological Features
There are often no recognizable gross abnormalities in the brains of
patients with Creutzfeldt-Jakob disease. Patients who survive for several
years have variable degrees of cerebral atrophy. The microscopical features
of Creutzfeldt-Jakob disease are spongiform degeneration and astrogliosis
 Figure 2A
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=F2>  and
Figure 2B
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=F2> ).
 27 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-27> )
Amyloid plaques occur in approximately 10 percent of cases of
Creutzfeldt-Jakob disease. These plaques are positive for antibodies against
PrPSc on immunohistochemical staining. ( 28
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-28> , 29
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-29> ) The
amyloid plaques in patients with Gerstmann-Straussler-Scheinker disease
consist of a dense core of amyloid surrounded by smaller globules of amyloid
( Figure 2
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=F2> ). A
characteristic feature of new variant Creutzfeldt-Jakob disease is the
presence of "florid plaques" composed of a core of PrPSc amyloid surrounded
by vacuoles ( Figure 2E
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=F2>  and
Figure 2F
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=F2> ).
Strains of Prions
The existence of prion strains raises the question of how heritable biologic
information can be encrypted in a molecule other than nucleic acid. ( 30
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-30> , 31
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-31> , 32
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-32> ) Strains
of prions have been defined by the rapidity with which they cause central
nervous system disease and by the distribution of neuronal vacuolation. ( 30
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-30> ) Patterns
of PrPSc deposition have also been used to characterize these strains. ( 33
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-33> , 34
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-34> ) There is
mounting evidence that the diversity of prions is enciphered in the
conformation of the PrPSc protein. ( 35
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-35> , 36
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-36> , 37
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-37> , 38
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-38> , 39
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-39> ) Studies
involving the transmission of fatal familial insomnia and familial
Creutzfeldt-Jakob disease to mice expressing a chimeric human-mouse PrP
transgene have shown that the tertiary and quaternary structure of PrPSc
contains strain-specific information. ( 37
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-37> ) Studies
of patients with fatal sporadic insomnia have extended these findings, ( 40
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-40> ) making
it clear that PrPSc acts as a template for the conversion of PrPC into
nascent PrPSc.
Sporadic, Genetic, and Infectious Forms of Prion Disease
Sporadic prion diseases might be initiated by a somatic mutation and in this
respect might develop in a manner similar to prion diseases caused by
germ-line mutations. In this situation, the mutant PrPSc must be capable of
recruiting wild-type PrPC, a process that may occur with some mutations but
is unlikely with others. ( 41
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-41> )
Alternatively, the activation barrier separating wild-type PrPC from PrPSc
may be crossed on rare occasions in the context of a large population of
people. ( 42
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-42> ) Twenty
mutations in the human PRNP gene have been found to segregate with inherited
prion diseases. ( 43
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-43> ) Missense
mutations and expansions in the octapeptide-repeat region of the gene cause
familial prion diseases. ( 15
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-15> , 16
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-16> , 17
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-17> , 18
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-18> , 19
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-19> )
Although infectious prion diseases constitute less than 1 percent of all
cases of prion disease, the circumstances surrounding the transmission of
these infectious illnesses are often dramatic ( Table 2
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=T2> ).
Ritualistic cannibalism has resulted in the transmission of kuru among the
Fore people of New Guinea, industrial cannibalism has been responsible for
bovine spongiform encephalopathy (BSE), or "mad cow disease," in Europe, and
an increasing number of patients have contracted new variant
Creutzfeldt-Jakob disease from prion-tainted beef products. ( 13
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-13> )
The restricted geographic and temporal distribution of cases of new variant
Creutzfeldt-Jakob disease raises the possibility that BSE prions have been
transmitted to humans. Although over 100 cases of new variant
Creutzfeldt-Jakob disease have been recorded, ( 44
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-44> , 45
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-45> ) no
dietary habits distinguish patients with this disease from apparently
healthy persons. Moreover, it is unclear why teenagers and young adults seem
to be particularly susceptible to the disease. These cases may mark the
start of an epidemic of prion disease in Great Britain like those of BSE and
kuru, or the number of cases of new variant Creutzfeldt-Jakob disease may
remain small, as with iatrogenic Creutzfeldt-Jakob disease caused by
cadaveric human growth hormone. ( 46
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-46> )
The most compelling evidence that new variant Creutzfeldt-Jakob disease is
caused by BSE prions comes from studies of mice expressing the bovine PrP
transgene. ( 47
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-47> ) The
incubation times, neuropathological features, and patterns of PrPSc
deposition in these transgenic mice are the same whether the inoculate
originated from the brains of cattle with BSE or from humans with new
variant Creutzfeldt-Jakob disease. ( 47
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-47> ) The
origin of BSE is still obscure, although epidemiologic studies indicate that
BSE probably arose from a single point source in the southwest of England in
the 1970s. ( 48
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-48> ) It
probably originated from a rare case of prion disease in either sheep (Scott
M, Prusiner SB: unpublished data) or cattle. ( 48
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-48> ) Once
established, the disease was spread in cattle by ingestion of
prion-contaminated meat and bone meal.
The accidental transmission of Creutzfeldt-Jakob disease to humans appears
to have occurred with corneal transplantation ( 49
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-49> ) and use
of contaminated electroencephalographic electrodes. ( 50
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-50> ) The same
improperly decontaminated electrodes that had caused Creutzfeldt-Jakob
disease in two young patients with intractable epilepsy were found to cause
Creutzfeldt-Jakob disease in a chimpanzee 18 months after their implantation
in the animal. ( 51
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-51> ) More
than 70 cases of Creutzfeldt-Jakob disease associated with the implantation
of dura mater grafts have been recorded. ( 52
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-52> ) One case
occurred after the repair of a perforated eardrum with a pericardial graft.
( 53 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-53> )
Prion-contaminated human growth hormone preparations derived from human
pituitary tissue have caused fatal cerebellar disorders with dementia in
more than 120 patients ranging in age from 10 to 41 years. ( 13
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-13> , 54
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-54> , 55
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-55> ) Four
cases of Creutzfeldt-Jakob disease have occurred in women who received human
pituitary gonadotropin. ( 56
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-56> )
Polymorphisms influence the susceptibility to sporadic, inherited, and
infectious forms of prion disease. Dominant negative alleles in
approximately 12 percent of the Japanese population ( 57
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-57> ) encode
for lysine at position 219 and interfere with the conversion of wild-type
PrPC into PrPSc. ( 58
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-58> , 59
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-59> ) Dominant
negative inhibition of prion replication has also been found in sheep, with
a substitution of the basic residue arginine at position 171. ( 60
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-60> , 61
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-61> )

Other Neurodegenerative Diseases

Like cases of the prion diseases, most cases of Alzheimer's disease,
Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal
dementia are sporadic; 10 percent or less are inherited. Although age is the
most important risk factor in all these sporadic forms of disease, the
factors that initiate neurodegeneration remain unknown. In the prion
diseases, the initial formation of PrPSc leads to an exponential increase in
the protein, which can be readily transmitted to another host. In the other
neurodegenerative diseases, the events that lead to the production of
aberrantly processed proteins, as well as the driving forces that sustain
their accumulation, are unknown. It is important to stress that in contrast
to the prion diseases, Alzheimer's disease, Parkinson's disease, amyotrophic
lateral sclerosis, and frontotemporal dementia are not infectious and have
not been transmitted to laboratory animals.
Alzheimer's Disease
A(beta)-amyloid plaques and neurofibrillary tangles are found in both
sporadic and inherited forms of Alzheimer's disease ( Table 3
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=T3> ).
Like familial prion diseases, familial Alzheimer's disease has an autosomal
dominant pattern of inheritance. Familial Alzheimer's disease can be caused
by a mutation in the gene for amyloid precursor protein (APP), presenilin 1,
or presenilin 2 ( Table 4
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=T4> ).
 62 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-62> )
Cleavage of amyloid precursor protein at residue 671 by (beta)-secretase and
at either residue 711 or residue 713 by (gamma)-secretase produces
A(beta)(1-40) and A(beta)(1-42), respectively. A(beta)(1-42) forms amyloid
fibrils readily and is thought to cause central nervous system dysfunction
before it is deposited in plaques. ( 63
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-63> , 64
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-64> , 65
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-65> )
Presenilin 1 and presenilin 2 may form complexes with at least one other
protein, nicastrin, a transmembrane neuronal glycoprotein, and these
complexes may contribute to the production of A(beta)(1-42). ( 66
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-66> )
The age of onset of both sporadic and familial forms of Alzheimer's disease
is modulated by allelic variants of apolipoprotein E. ( 67
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-67> ) Three
alternative allelic products of apolipoprotein E, denoted (epsilon)2,
(epsilon)3, and (epsilon)4, differ at amino acid residues 112 and 158. In
many persons with two (epsilon)4 alleles, Alzheimer's disease develops at
least a decade before it does in those with two copies of (epsilon)2, and
(epsilon)3 is associated with an onset of disease at an intermediate age.
 68 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-68> )
Frontotemporal Dementia and Pick's Disease
Mutations in the tau gene, which codes for tau, a protein associated with
microtubules, cause inherited forms of frontotemporal dementia and Pick's
disease. ( 69
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-69> , 70
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-70> , 71
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-71> ) As with
Alzheimer's disease, about 90 percent of cases of frontotemporal dementia
are sporadic, and the rest are familial. Straight filaments composed of
hyperphosphorylated mutant tau have been found in the brains of patients
with familial frontotemporal dementia ( Table 3
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=T3> ).
 72 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-72> ) In
some cases, neurofibrillary tangles composed of paired helical filaments
have been found; the formation of these filaments seems to depend on the
specific mutation and on the specific isoform of the protein ( Table 4
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=T4> ).
 73 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-73> ) In
sporadic cases of frontotemporal dementia, aggregates of tau are uncommon.
Approximately 15 percent of patients with frontotemporal dementia have Pick
bodies, ( 74
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-74> ) which
are intracellular collections of partially degraded (ubiquinated) tau
fibrils in the brain. ( 75
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-75> ) As with
frontotemporal dementia, most cases of Pick's disease are sporadic. Other
disorders caused by the misprocessing of tau include progressive
supranuclear palsy, progressive subcortical gliosis, and corticobasal
degeneration. ( 73
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-73> , 75
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-75> , 76
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-76> , 77
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-77> )
Parkinson's Disease
Most cases of Parkinson's disease are sporadic, ( 78
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-78> , 79
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-79> ) but both
sporadic and familial forms of the disease are characterized by protein
deposits in the central nervous system. Mutations in the gene for
(alpha)-synuclein have been found in patients with familial Parkinson's
disease. ( 80
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-80> ) In both
sporadic and familial cases, antibodies to (alpha)-synuclein, a presynaptic
intracellular protein, stain Lewy bodies in neurons of the substantia nigra.
( 81 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-81> )
Whereas the inheritance of Parkinson's disease due to mutations in the
(alpha)-synuclein gene is autosomal dominant, a childhood form of the
disease due to mutations in the gene for ubiquitin-protein ligase (parkin)
is a recessive disorder ( Table 4
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=T4> ).
 82 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-82> )
Parkin seems to promote the degradation of certain neuronal proteins, and
selective nitration of (alpha)-synuclein has been observed in Lewy bodies.
 83 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-83> )
Parkinson's disease in older persons is associated with a high incidence of
dementia. ( 84
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-84> ) At
autopsy, the brains of such patients often have the neuropathological
hallmarks of both Alzheimer's disease and Parkinson's disease.
Immunohistochemical studies showing the presence of (alpha)-synuclein in
cortical Lewy bodies have helped resolve the conundrum of how a patient
could have insufficient numbers of plaques and neurofibrillary tangles for
the diagnosis of Alzheimer's disease but still have dementia. The presence
of these (alpha)-synuclein deposits, alone or in combination with changes
that are characteristic of Alzheimer's disease, may be the second most
common form of neurodegeneration, accounting for 20 to 30 percent of cases
of dementia among persons over the age of 60 years. ( 85
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-85> , 86
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-86> ) A small
number of younger persons with Parkinson's disease also have dementia due to
diffuse Lewy body disease. ( 87
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-87> )
Amyotrophic Lateral Sclerosis
Although most cases of amyotrophic lateral sclerosis are sporadic, familial
cases have been identified. ( 88
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-88> , 89
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-89> , 90
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-90> ) In
approximately 20 percent of familial cases of amyotrophic lateral sclerosis,
there are mutations in the gene for cytoplasmic superoxide dismutase type 1
(SOD1) ( Table 4
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=T4> ).
 91 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-91> )
Moreover, deposits of SOD1 in the central nervous system have been found in
both sporadic and familial cases of amyotrophic lateral sclerosis. ( 92
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-92> ) Although
in some cases abnormal collections of neurofilaments have been seen in
degenerating motor neurons, no familial cases have been shown to be due to
mutations in neurofilament genes. ( 92
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-92> )
Huntington's Disease and Spinocerebellar Ataxias
Unlike Alzheimer's disease, frontotemporal dementia, Parkinson's disease,
amyotrophic lateral sclerosis, and the prion diseases, which in most cases
are sporadic, all cases of Huntington's disease and of spinocerebellar
ataxia are caused by expanded polyglutamine repeats ( Table 4
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=T4> ).
 93 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-93> , 94
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-94> , 95
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-95> ) But
these diseases are similar to the inherited forms of Alzheimer's disease,
frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis,
and the prion diseases in that they are usually manifested as neurologic
deficits in adulthood, even though the expression of the mutant gene
products in the central nervous system begins early in life. Childhood forms
of Huntington's disease and spinocerebellar ataxia are known to be due to
large expansions of the causative triplet repeats. ( 94
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-94> , 96
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-96> , 97
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-97> )
Transgenic Mouse Models
Although virtually every facet of the human and animal prion diseases has
been reproduced in transgenic mice, attempts to develop transgenic models
for the other neurodegenerative diseases have proved more difficult. Despite
the lack of perfect transgenic models for Alzheimer's disease, Parkinson's
disease, amyotrophic lateral sclerosis, frontotemporal dementias,
Huntington's disease, and the spinocerebellar ataxias, many aspects of these
human disorders have been reproduced. Mice expressing transgenes carrying
mutations found in the inherited forms of these neurodegenerative diseases
develop disorders with many of the neuropathological features that
characterize the corresponding human illnesses ( Table 3
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=T3>  and
Table 4
<http://www.nejm.com/content/figs/2001/0344/0020/1516.asp?section=T4> ).

Diagnostic Tests

There is an urgent need for a rapid, antemortem test for prions in humans
and livestock. A highly sensitive quantitative immunoassay has been
developed on the basis of antigens that are exposed in PrPC but buried in
PrPSc. Unlike earlier immunoassays for PrPSc, this conformation-dependent
immunoassay does not require limited proteolysis to hydrolyze PrPC before
the protease-resistant core of PrPSc (PrP 27-30) is measured. ( 38
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-38> ) This
assay has been used to identify a new form of PrPSc, which is
protease-sensitive (sPrPSc).
A diagnostic test would be valuable for distinguishing between early
Alzheimer's disease and depression in older persons, since both disorders
are so common. In Alzheimer's disease, frontotemporal dementia, Parkinson's
disease, and the prion diseases, computed tomography or magnetic resonance
imaging may show normal findings or cortical atrophy. In patients with
Alzheimer's disease, widespread atrophy with enlarged ventricles is often
seen, especially late in the disease, but this finding is not diagnostic.
Many elderly persons with normal cognition have similar radiographic
findings. ( 98
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-98> , 99
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-99> ) Although
many patients with Creutzfeldt-Jakob disease have elevated levels of protein
14-3-3 in cerebrospinal fluid, this finding is not specific for the
diagnosis. ( 100
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-100> , 101
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-101> )
Attempts to measure A(beta)(1-40) in blood and urine as diagnostic tests
have been unrewarding, ( 102
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-102> ) but the
use of fluorescence correlation spectroscopy to measure A(beta)(1-40) in
cerebrospinal fluid may provide a reliable diagnostic test for Alzheimer's
disease. ( 103
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-103> )
Whereas electroencephalographic studies are not useful for the diagnosis of
Alzheimer's disease, frontotemporal dementia, or Parkinson's disease, they
are often useful for the diagnosis of Creutzfeldt-Jakob disease. Repetitive,
high-voltage, triphasic and polyphasic sharp discharges are seen in most
advanced cases of Creutzfeldt-Jakob disease, but their presence is often
transient. ( 25
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-25> , 101
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-101> , 104
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-104> , 105
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-105> ) As the
disease progresses, normal background rhythms become fragmentary and slower.
Hashimoto's thyroiditis should always be considered in the differential
diagnosis of Creutzfeldt-Jakob disease, ( 106
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-106> ) since
the former disorder is a treatable autoimmune disease whereas
Creutzfeldt-Jakob disease is not. The clinical and neuropathological
findings in these two disorders can be quite similar, raising the
possibility that protein misprocessing underlies both degenerative and
autoimmune diseases.

Prevention and Treatment

With the exception of levodopa, which ameliorates the symptoms of
Parkinson's disease but does not halt the underlying degeneration, there are
no effective therapies for neurodegenerative diseases. The history of
successful attempts to prevent or reverse protein misprocessing is extremely
limited. ( 107
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-107> )
Developing new drugs directed to specific regions of the central nervous
system will be challenging.
Preventing Abnormal Processing of Proteins and Enhancing Their Clearance
Structure-based drug design based on dominant negative inhibition of prion
formation has resulted in the development of several compounds. ( 108
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-108> )
However, the task of exchanging polypeptide scaffolds for small heterocyclic
structures without the loss of biologic activity remains difficult. Whether
this approach to preventing the aberrant processing of proteins will lead to
the development of new treatments for Alzheimer's and Parkinson's diseases,
as well as other neurodegenerative disorders, remains to be established.
Several compounds can eliminate prions from cultured cells. A class of
compounds known as "dendrimers" seems particularly effective in this regard.
( 109 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-109> )
Some drugs delay the onset of disease in animals that have been inoculated
with prions if the drugs are given around the time of the inoculation. ( 110
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-110> ) A novel
approach to treating Alzheimer's disease has been developed in transgenic
mice that overexpress a mutant APP gene. Immunization of these mice with the
A(beta) peptide or injection of antibodies to A(beta) reduces plaque
formation. ( 111
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-111> ) Whether
this approach will prove fruitful in patients is unknown.
Replacement Therapy
Because the neurodegeneration in Parkinson's disease is confined largely to
the substantia nigra, especially early in the disease process, replacement
therapy with levodopa has proved useful; in many patients, however, the
disease eventually becomes refractory to levodopa. ( 112
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-112> ) Similar
approaches to the treatment of Alzheimer's disease have been disappointing,
primarily because the disease process is so widespread. Similarly, the
widespread neuropathological changes in amyotrophic lateral sclerosis,
frontotemporal dementia, and prion diseases make it unlikely that
replacement therapy will be successful.

Speculation on the Spectrum of Degenerative Diseases

It is tempting to speculate that abnormal processing of neuronal proteins
also occurs in other diseases of the central nervous system, such as
schizophrenia, bipolar disorders, autism, and narcolepsy. ( 113
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-113> ) Most
cases of these diseases are sporadic, but a substantial minority appear to
be familial. The absence of neuropathological changes in these conditions
has impeded phenotypic analysis. In a group of patients with inherited
frontotemporal dementia who have a mutation in the tau gene, alcoholism and
Parkinson's disease are prominent features. ( 114
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-114> )
Whether multiple sclerosis is also the result of defective processing of
brain proteins is unknown. ( 115
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-115> ) The
immune system features prominently in the pathogenesis of multiple
sclerosis, and it is often argued that this disease is a T-cell-mediated,
autoimmune disorder. Antibody-mediated demyelination has been found in some
cases of multiple sclerosis, ( 116
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-116> ) and in
others, degeneration of oligodendrocytes has been observed, with little or
no evidence of immune-mediated damage. ( 117
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-117> ) Perhaps
ulcerative colitis, Crohn's disease, rheumatoid arthritis, type 1 diabetes
mellitus, and systemic lupus erythematosus ought to be considered disorders
of protein processing in which misfolded proteins evoke an autoimmune
response.
The systemic amyloidoses share important features with the neurodegenerative
diseases. In primary amyloidosis, immunoglobulin light chains form amyloid
deposits that can cause cardiomyopathy, renal failure, and polyneuropathy.
 118 <http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-118> ) In
response to chronic inflammatory diseases, the serum amyloid A protein is
cleaved and forms the amyloid A protein, which is deposited as fibrils in
the kidney, liver, and spleen. The most common form of systemic hereditary
amyloidosis is caused by the deposition of mutant transthyretin. Also
noteworthy are amylin deposits in the (beta)-islet cells of patients with
type 2 diabetes mellitus. These deposits contain amyloid fibrils that are
composed of the amylin protein.

The Future

As life expectancy continues to increase, the burden of degenerative
diseases is growing. Developing effective means of preventing these
disorders and of treating them when they do occur is a paramount challenge.
The problems caused by Alzheimer's disease and Parkinson's disease are
already so great that if the prevalence of these maladies continues to
increase in accordance with the changing demographic characteristics of the
world population, they will bankrupt both developed and developing countries
over the next 50 years. It is remarkable to think that by the year 2025,
more than 65 percent of persons over the age of 65 years will be living in
countries that are now designated as developing countries. ( 119
<http://www.nejm.com/content/refs/2001/0344/0020/1516.asp#ref-119> ) Unless
effective methods of prevention and treatment are developed, this enormous
population of people will be subjected to the same risks of Alzheimer's
disease, Parkinson's disease, and other neurodegenerative disorders as are
older persons currently living in the most affluent countries.
Over the past two decades, remarkable progress has been made in elucidating
the causes of neurodegenerative diseases, and the time has come to intensify
the search for drug targets and for compounds that interrupt the disease
processes. Drugs that block the mishandling of a particular protein may be
most effective for certain disorders; for others, drugs that enhance the
clearance of an aberrant protein or fragment may prove most useful.
Regardless of the therapeutic approach, accurate, early detection of
neurodegeneration will be extremely important so that drugs can be given
before substantial damage to the central nervous system has occurred.
However, the enormity of these tasks -- developing useful diagnostic tests
and discovering effective therapies -- should not be underestimated.
Supported by grants from the National Institutes of Health (NS14069,
AG02132, and AG10770), the American Health Assistance Foundation, and the
Leila and Harold Mathers Foundation.



  _____


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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.