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Folding Fixers

Misshapen proteins are implicated in a wide array of disorders. Here are just a few, and how drugs might restore function to errant proteins.

By Lauren Ware // Spring 2010
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LOSS-OF-FUNCTION DISEASES:

Occur when a misfolded protein can’t achieve its intended purpose, either because it’s not functioning properly or because it’s targeted for early destruction. A genetic mutation is typically the cause.



 

DISEASE

HOW MISFOLDING MAY BE INVOLVED

POTENTIAL INTERVENTION

CYSTIC FIBROSIS In the most common mutation, ΔF508, a missing amino acid causes the CFTR protein to fold improperly, leading to its destruction. WIthout CFTR, ion transport across the cell membrane is impaired, affecting the amount of water in epithelial tissues and clogging the lungs and pancreatic ducts with mucus. Pharmacologic chaperones (molecules that partially repair a misfolded protein, ushering it out of the cell); proteostasis regulators (molecules that stimulate chaperone production and/or affect signaling pathways, increasing the probability of proper protein folding)
LYSOSOMAL STORAGE DISEASES (Gaucher’s disease, Fabry disease and more than 40 others)
A mutation in a lysosomal enzyme causes it to misfold and be destroyed. Lysosomal enzymes break down discarded components in the cell for reuse; without them, these components build up and cause tissue damage. The specific symptoms depend on which enzyme has mutated and was destroyed. Pharmacologic chaperones; proteostasis regulators


GAIN-OF-FUNCTION DISEASES:

Occur when a misfolded protein broken down by the cell is reassembled into an aggregate that causes cellular damage. These diseases are often associated with aging, though genetic mutation may also be at fault.



 

DISEASE

HOW MISFOLDING MAY BE INVOLVED

POTENTIAL INTERVENTION

HUNTINGTON’S DISEASE
A mutation inserts extra glutamine, an amino acid, in the huntingtin protein. The extra glutamine causes the misformed protein to stick to other proteins, damaging brain cells. Kinetic stabilizers (molecules that bind to the misfolded protein, preventing it from breaking apart); proteostasis regulators
PARKINSON’S DISEASE
A protein in the brain, called Α-synuclein, misfolds, breaks apart and re-forms into aggregates that poison neurons. Kinetic stabilizers; proteostasis regulators
HUNTINGTON’S DISEASE
A mutation inserts extra glutamine, an amino acid, in the huntingtin protein. The extra glutamine causes the misformed protein to stick to other proteins, damaging brain cells. Kinetic stabilizers (molecules that bind to the misfolded protein, preventing it from breaking apart); proteostasis regulators
ALZHEIMER’S DISEASE
Amyloid precursor protein is broken down into smaller proteins that misfold and stick together in clumps called oligomers, which eventually form the plaques in the brain that are characteristic of the disease. Kinetic stabilizers; proteostasis regulators
TTR AMYLOID POLYNEUROPATHY
Mutated TTR becomes unstable and dissociates into smaller components that partially unfold and then stick together, forming tangles of protein called amyloids. The amyloids cause damage to nerve tissues. Kinetic stabilizers; proteostasis regulators
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