section 4.7
Protein Folding and Associated Diseases
63
directed at inhibiting or decreasing the formation of neu-
rotoxic peptides. In addition, drugs that selectively digest
the aggregated peptides may prove useful. An experimen-
tal vaccine which contains AP peptide administered to
plaque-producing mice leads to less plaque formation in
younger mice and the disappearance of plaques in the
older mice. The alterations in the plaque formation in mice
were associated with preservation of memory and learning
ability. The vaccination did not trigger an autoimmune re-
sponse or toxic reaction in the experimental animals. Thus,
these studies have provided impetus for the development
of a human vaccine.
In evaluating a patient for Alzheimer’s disease, it is es-
sential that other treatable causes of dementia be excluded
by determining critical biochemical and clinical parame-
ters. Some of the treatable, relatively common abnormali-
ties that produce dementia include drug abuse, electrolyte
imbalance, thyroid abnormalities, and vitamin B
1 2
defi-
ciency; less common abnormalities are tumor, stroke, and
Wernicke’s encephalopathy.
Transthyretin amyloidosis
(also called familial amy-
loid polyneuropathy) is an autosomal dominant syndrome
characterized by peripheral neuropathy. This disease re-
sults from one of five mutations identified thus far in the
gene for transthyretin. Transthyretin is also called
prealbu-
min
(although it has no structural relationship to albumin)
because it migrates ahead of albumin in standard elec-
trophoresis at pH
8
.
6
. Transthyretin is synthesized in the
liver and is a normal plasma protein with a concentration of
20-40 mg/dL. It transports thyroxine and retinol binding
protein (Chapter 38). The concentration of transthyretin is
significantly decreased in malnutrition and plasma levels
are diagnostic of disorders of malnutrition (Chapter 17).
The gene for transthyretin resides on chromosome 18
and it is expressed in a constitutive manner. The pri-
mary structure of transthyretin consists of 127 amino acid
residues and eight /3-sheet structures arranged in an an-
tiparallel conformation on parallel planes (Figure 4-15).
Protein folding disorders of an unusual nature may
account for a group of
transmissible spongiform en-
cephalopathies
(TSE) involving proteins called
prions
(PrP). These disorders, known as
prion diseases,
are all
characterized by amyloid deposition in the brain of ani-
mals and humans. The clinical features include neurologi-
cal symptoms with loss of motor control, dementia, paral-
ysis, and wasting. Incubation periods for prion diseases are
months in animals and years in humans. No treatments are
available for any of these diseases. TSEs occur in several
species of animals and humans, and animal models have
been essential in deciphering the molecular basis of these
diseases. Examples of prion diseases occuring in animals
and humans are:
FIGURE 4-15
The structure of transthyretin. The molecule contains eight antiparallel
/1-strands (A-H) arranged in two parallel planes. The circulating form of
transthyretin is a tetramer. Some mutations in the transthyretin gene are
associated with amyloidosis and eight of the amino acid alterations causing
this disease are indicated. In plasma, transthyretin is a tetramer composed
of identical monomers. It appears that mutations cause the monomeric
unfolded intermediate of transthyretin to aggregate into an insoluble
/1-amyloid fibril formation.
Cats
:
transmissible feline
encephalopathy
Cows
:
bovine spongiform
encephalopathy
(BSE)
Mink
:
transmissible mink
encephalopathy
Mule deer and elk:
chronic wasting disease
Sheep
:
scrapie
Humans
:
Creutzfeld-Jakob disease
(CJD),
Kuru, fatal-familial
insomnia syndrome,
and
Gerstmann-Straussler-
Schenker disease
TSEs can exhibit inherited, infectious and sporadic pre-
sentations. Additionally, the inherited disease can also be
infectious. CJD occurs both as an inherited autosomal
dominant disorder and in a transmissible form. In the “pro-
tein only” hypothesis, the abnormal prion protein, either
introduced from external sources or produced by the mu-
tated prion protein gene, affects normal protein folding
and shifts the prion protein folding towards the formation
