section
4.7
Protein Folding and Associated Diseases
61
T A B L E 4-1
Examples of Protein Folding Diseases*
Disease
Mutant protein/protein involved
Molecular phenotype
Inability to fold
Cystic fibrosis
CFTR
Misfolding/altered Hsp70
and calnexin interactions
Marfan syndrome
Fibrillin
Misfolding
Amyotrophic lateral sclerosis
Superoxide dismutase
Misfolding
Scurvy
Collagen
Misfolding
Maple syrup urine disease
a
-Ketoacid dehydrogenase complex
Misassembly/misfolding
Cancer
p53
Misfolding/altered
Hsp70 interaction
Osteogenesis imperfecta
Type I procollagen pro
a
Misassembly/ altered
BiP expression
Toxic folds
Scrapie/Creutzfeldt-Jakob/
Prion protein
Aggregation
familial insomnia
Alzheimer’s disease
ß
-Amyloid
Aggregation
Familial amyloidosis
T ransthyretin/lysozyme
Aggregation
Cataracts
Crystalline
Aggregation
Mislocalization owing to misfolding
Familial hypercholesterolemia
LDL receptor
Improper trafficking
a
j - Antitrypsin deficiency
a
j - Antitrypsin
Improper trafficking
Tay-Sachs disease
ß
-Hexosaminidase
Improper trafficking
Retinitis pigmentosa
Rhodopsin
Improper trafficking
Leprechaunism
Insulin receptor
Improper trafficking
‘Reproduced with permission from P. J. Thomas, B-H. Qu and P. L. Pedersen.
T ren d s in B io ch e m ic a ls S c ien ces
20,456 (1995).
stability, and independent function was described by
Alois
Alzheimer
and is known as
Alzheimer’s disease
(AD). Age
is an important risk factor for AD; it affects 10% of persons
over 65 years of age and about 40% of those over age 85.
The characteristic neuropathological changes include for-
mation of extracellular neuritic plaques and intraneuronal
tangles with associated neuronal loss in hippocampus and
neocortex (Figure 4-14).
The major constituent of the extracellular plaques is
amyloid ft-protein
(A/3), which aggregates into
8
nm fil-
aments. A
/6
is a peptide of 40 or 42 amino acid residues
and is proteolytically derived from a transmembrane gly-
coprotein known as
fi -amyloid precursor protein
(/3APP).
The enzymes that cleave /SAPP to A
/6
are known as sec-
retases. /SAPP is widely expressed, particularly in brain,
and its gene has been localized to chromosome 21q. Two
major observations have aided in understanding the role of
A
/ 6
peptides in the pathology of Alzheimer’s disease. The
first is that patients with
Down syndrome
have trisomy 21
(i.e., three chromosome 21’s instead of two), exhibit
Aft
deposits, and develop classical features of Alzheimer’s
disease at age 40 years or earlier. Second, several mis-
sense mutations in /1APP have been identified in cases
of autosomal dominant Alzheimer’s disease. These dom-
inant mutations in /SAPP adversely affect the action of
secretases either by increasing the absolute rate of
Aft
ex-
cretion (N-terminal mutations) or by increasing the ratio
A/3
4 2
to A/
6 4 0
(C-terminal mutations).
Inherited disorders of Alzheimer’s disease represent
less than 1% of all cases. The A/S peptides aggregate to
form /
6
-structures leading to fibrils. The A/
6 4 2
peptides are
more neurotoxic and produce toxic effects by many inter-
related mechanisms. These may involve oxidative injury,
changes in intracellular Ca2+ homeostasis, cytoskeletal re-
organization, and actions by cytokines.
The intraneuronal tangles are bundles of long paired he-
lical filaments that consist of the microtubule-associated
protein tau. The normal function of tau protein is
