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Science News

Protein Shown to Protect against Parkinsonís by Helping Clear Out Other Damaged Protein from Brain

A protein involved in gathering and removing cellular waste plays a key role in Parkinson’s disease (PD), according to new research published in the February 8 edition of The Journal of Neuroscience.  Scientists believe the protein protects the brain against the build-up of alpha-synuclein, a key player in the development of Parkinson’s.

The beneficial protein, called VPS-41, was previously identified after sorting through hundreds of others.  It was found to be the most protective against the toxic aggregation and clumping of alpha-synuclein that occurs in Parkinson’s.  In Parkinson’s, cells cannot get rid of this excess alpha-synuclein and it accumulates into Lewy bodies, which are the pathological hallmark of the disease.  This finding fit with the known function of VPS-41—the removal of cellular waste from neurons – suggesting that VPS-41 could clear excess alpha-synuclein from the cell.  Subsequent studies in animal and human cell cultures, demonstrated that VPS-41 not only protected against alpha-synuclein accumulation but also protected dopaminergic neurons, the neurons lost in Parkinson’s, from dying.  However, the exact mechanism by which VPS-41 protected against alpha-synuclein accumulation was unknown.

In this study, the team of Kim A. Caldwell, Ph.D., and Guy A. Caldwell, Ph.D., and colleagues, from the University of Alabama at Birmingham carefully studied the relationship between VPS-41, alpha-synuclein levels, and cell death in both a worm model of PD and in human neuron cell cultures, to determine exactly what parts of VPS-41 led to its protective qualities.  The team also investigated the potential link between two rare genetic variants of the human VPS-41 gene and Parkinson’s.

Results

  • Introducing the protein VPS-41 into cells reduced the build-up of alpha-synuclein
  • Dopaminergic neurons like those lost in Parkinson’s survived better after adding VPS-41 protein to the cultures
  • Two protective components of the VPS-41 proteins were essential for the removal of cellular waste and the ability to protect cells from excess alpha-synuclein.  If either was missing or damaged, the VPS-41 protein could not remove the excess alpha-synuclein.
  • One of these protective components was damaged in two rare but naturally occurring variants in the in the human VPS-41 gene. Scientists showed that these variants also eliminated the protein’s protective qualities.  Both variants have been found in about two percent of humans.

What Does it Mean?

The results make clear that VPS-41 is protective against alpha-synuclein-related cell death in cellular models of Parkinson’s.  The study found robust evidence of this protective effect in multiple models of Parkinson’s, including in human brain cells.  In addition, the study identified human genetic variants that, in these models, eliminate the protective effect of VPS-41.  This suggests there may be a previously unidentified genetic susceptibility factor for Parkinson’s.

If the role of VPS-41 can be confirmed in mice models of alpha-synuclein and later in people with Parkinson’s, it is possible that increasing the effectiveness or quantity of VPS-41 could represent an important new approach to clearing alpha-synuclein from brain cells.  In so doing, this could create a potential new method for treating Parkinson’s.

Reference:
Harrington, A.J., Yacoubian, T.A., Slone, S.R., Caldwell, K.A., Caldwell, G.A. Functional Analysis of VPS41-Mediated Neuroprotection in Caenorhabditis elegans and Mammalian Models of Parkinson’s Disease. The Journal of Neuroscience, 8 February 2012, 32(6): 2142-2153; doi:10.1523/JNEUROSCI.2606
-11.2012.

Source Date: Mar 12 2012