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normally, causing them to clump together and form toxic deposits in neurons. The
disease can also arise if neurons make too much of the normal protein, pushing the
protein folding capacity of chaperones beyond their normal limits. Other genes
counteract the effects of misfolded ataxin and provide potential targets for future
human therapies.
In many cases, the mutations are not so severe as to render the protein biologi-
cally inactive. Rather, the mutations often result in only subtle protein-folding
abnormalities. In the case of the CFTR protein, a mutation leading to the loss of a
single amino acid is responsible for the diseased state in the majority of individuals
with cystic fi brosis. A number of low-molecular-weight compounds, all of which
are known to stabilize proteins in their native conformation, are effective in rescuing
the folding and/or processing defects associated with different mutations that often
lead to human disease. Recent reports have suggested that some of the major neuro-
degenerative pathologies could be gathered under a unifying theory stating that all
diseases linked to protein misfolding could be due to the inherent toxicity associated
with protein aggregates.
Therapies for Protein Misfolding
A number of low-molecular-weight compounds, all of which are known to stabilize
proteins in their native conformation, are effective in rescuing the folding and/or
processing defects associated with different mutations that often lead to human dis-
ease. The small compounds being developed to correct the misfolding of proteins
are called chemical chaperones, pharmacological chaperones or pharmacoperones.
Promising results have been achieved in a small clinical trial to treat nephrogenic
diabetes insipidus, and trials are under way of patients with emphysema and chronic
liver disease, conditions that can be caused by the same misfolded protein.
Encouraging in vitro results have been reported for cystic fi brosis, Fabry disease,
hypercholesterolemia, and the aggregation of prions in spongiform encephalopathy.
In mice, the mutant p53 tumor-suppressor protein has been successfully treated.
Potential also exists to correct misfolding in retinitis pigmentosa, sickle cell disease,
thalassemia, cataracts, and hypertrophic cardiomyopathy. This approach may offer
an alternative to antibody treatments and gene therapy. Some other examples of
recent achievements are as follows.
Several mutations of the GnRH (gonadotropin-releasing hormone) have been
identifi ed in patients with hypogonadotropic hypogonadism (HH) and some of the
missense mutations can be rescued with a GnRH peptidomimetic antagonist that
acts as folding template, stabilizing (otherwise) misfolded GnRHR receptor mutants
and thereby restoring function. Antagonist can be removed after the correctly folded
protein reaches the cell surface and the receptor will function normally, as measured
by its participation in activating the production of inositol phosphate and release of
intracellular calcium. This suggests that the drug need not interact at the same site
as the native ligand; it can stabilize the protein allosterically. The pharmacoperone