(PrPSCprotein), Parkinson’s disease (α-synuclein), Pick’s disease (tau), Huntington’s
disease (polyglutamine-containing protein), and familial amyotrophic lateral sclerosis
(SOD1), share a single mechanistic feature—the aggregation and deposition of an
abnormal protein product. Following the identification of various genes implicated in
the molecular pathogenesis of these diseases, it has become clear that the major effect
of mutations in these genes is the abnormal processing and accumulation of misfolded
protein products, leading to neuronal inclusions and plaques. These insights into toxic
protein accumulation and abnormal protein deposition may permit the rational design
of effective therapies. To demonstrate these design principles, two diseases will be
discussed: prion-induced dementia and Alzheimer’s dementia.
8.3.1.1 Protein Folding Diseases: Prion-Induced Dementia
Prion diseases have attracted immense attention over the past decade. This attention
was prompted, in part, by the outbreak of “mad cow disease” in the United Kingdom,
an outbreak that ultimately involved humans. More recently, the identification of
cows with mad cow disease in North America has emphasized the widespread nature
of this problem.
The most common prion disease is sporadic Creutzfeldt–Jakob Disease (CJD). Less
common prion-based diseases include Gerstmann–Straussler–Scheinker disease, fatal
familial insomnia, and familial CJD. Unlike other neurodegenerative diseases, prion-
based disorders are uniquely characterized by the property of transmissibility.
Clinically, CJD is characterized by a rapidly progressive dementia accompanied variably
by early-onset seizures, insomnia, disordered movements, and psychiatric disturbances;
the disease is uniformly fatal. Pathologically, the brains of people who have died from
prion diseases show neuronal loss, gliosis (i.e., scarring) and spongiform vacuolation
(i.e., the brain contains many microscopic holes, giving it a “sponge-like” appearance;
hence the alternative name of spongiform encephalopathyfor prion diseases).
Histochemically, another pathological feature of prion disease is the abnormal accu-
mulation of an amyloid-like material composed of prion protein (PrP), which is encoded
by a single gene on the short arm of chromosome 20.
The abnormal deposits found in the brains of CJD victims consist of an abnormal iso-
form of PrP. Prion protein is normally found in cells. Detailed structural studies show that
normal cellular PrP (PrPC) is a soluble protein whose conformation is rich in α-helices
with very little β-sheet. The PrP protein extracted from the brains of CJD victims (i.e.,
PrPSC) is identical in primary amino acid sequence to the normal PrP (PrPC). However,
PrPSChas a much greater content of β-sheet conformation with little α-helical structure.
Thus PrPSCis neurotoxic because of its three-dimensional structure. When the prion
protein is predominantly in an α-helical conformation it is nontoxic; when the prion
protein is predominantly in a β-sheet conformation, it kills neurons. The prion protein
is thus made neurotoxic not by its amino acid composition but by its conformation. This
concept is both fascinating and terrifying. Prion diseases are transmissible; thus prions
are infectious agents. However, prions are not like bacteria or viruses, or other infec-
tious microbes—they are simply protein molecules. Prions are notmicrobes with cell
membranes and nucleic acids; they are not “living things.” Indeed, prions are not even
infectious molecules, they are infectious molecular shapes.
514 MEDICINAL CHEMISTRY