'Clump-Busting' Molecule Targets Misfolded Proteins in ALS

by Amy Madsen on Mon, 2014-01-27 09:49

An MDA-supported team of researchers has shown that 'reprogrammed' versions of the yeast protein HSP104 can reverse protein misfolding and clumping in amyotrophic lateral sclerosis  

With MDA support, James Shorter is exploring the possibility that breaking apart protein clumps (aggregates) and returning misfolded proteins to their normal state may be therapeutic in ALS.
Article Highlights:
  • A common feature in amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases is the presence in nerve cells of improperly folded proteins that clump together, forming aggregates.
  • Breaking up aggregates and helping misfolded proteins re-fold into their proper shape may be an effective therapeutic strategy for preventing or suppressing nerve-cell death in ALS.
  • In tests conducted in yeast cells, modified versions of the yeast protein HSP104 broke apart aggregates containing TDP43 and FUS — two proteins known to misfold and aggregate in ALS — and helped the misfolded proteins return to their proper form.
  • The findings represent a first step toward the potential development of clump-busting therapies for ALS and other neurodegenerative diseases.

In studies conducted in yeast cells, modified versions of a common yeast protein broke up aggregates (clumps) of improperly folded proteins known to be involved in amyotrophic lateral sclerosis (ALS) and helped the misfolded proteins re-fold into their normal shape, an MDA-supported team of researchers reports.

Misfolded proteins are found in the motor neurons of nearly all people with ALS, and studies suggest that aggregates may play a central role in the disease process. Although one possibility is that aggregates play a protective role — "mopping up" misfolded proteins as part of a cellular defense mechanism — a growing body of evidence suggests that the aggregates are toxic and that they contribute to the damage and eventual death of nerve cells.

The new findings represent a first step toward the potential development of clump-busting therapies for ALS and other neurodegenerative diseases. 

Modified HSP104 effectively targeted ALS-associated proteins

MDA-supported researcher James Shorter, associate professor of biochemistry and biophysics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and colleagues, engineered yeast cells to produce different versions of HSP104, a "chaperone" protein known to deconstruct protein clumps and help return misfolded proteins to their normal state in yeast.

In tests, the modified HSP104 broke apart clumps containing TDP43 and FUS — two proteins known to misfold and aggregate in ALS — and alpha-synuclein, a protein that misfolds and clumps together in Parkinson's disease. In addition, the modified HSP104 helped return misfolded TDP43, FUS and alpha-synuclein proteins to their proper form.

In further studies conducted in a worm model of Parkinson's disease, the team showed that breaking apart clumps and restoring misfolded alpha-synuclein proteins to their correct shape using modified HSP104 appeared to prevent nerve-cell death.

A first step in potential therapy development

Because of its ability to return disease-associated proteins to their normal form, modified HSP104 may hold potential for halting and reversing neurodegenerative diseases like ALS, the team suggests.

First, however, the strategy must be tested in animal models to determine whether introducing a foreign protein produces harmful effects. (No human version of HSP104 exists.)

In addition, aside from HSP104's ability to deconstruct protein clumps, "the other major goal from a bioengineering viewpoint is to make the tweaked HSP104 specific in what it targets, because all the variants we have at the moment seem to work across the board," Shorter said in a Jan. 16, 2014 press release

Further engineering is needed to develop more refined versions of HSP104 that specifically target single proteins, in order to avoid off-target effects.

The team published its findings online Jan. 16, 2014, in the journal Cell.

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