CANADA: U of T led research team uncovers evolutionary origins of prion disease gene

28.sep.09
University of Toronto
Jennifer Little

TORONTO, ON -- A University of Toronto-led team has uncovered the
evolutionary ancestry of the prion gene, which may reveal new
understandings of how the prion protein causes diseases such as bovine
spongiform encephalopathy (BSE), also known as "mad cow disease."
Diseased prion proteins are responsible for the fatal neurodegenerative
Creutzfeldt-Jakob disease (CJD) in humans, and BSE, scrapie and chronic
wasting disease (CWD) in livestock. Overall, this work holds promise for
efforts to reveal the physiological function of members of the prion
protein family and may provide insights into the origins and underlying
constraints of the conformational changes associated with prion
diseases. The study was published today, September 28, 2009, in the
online journal PLoS ONE.
Principal investigator Gerold Schmitt-Ulms (Centre for Research in
Neurodegenerative Diseases; Department of Laboratory Medicine and
Pathobiology, U of T) and his graduate student Sepehr Ehsani teamed up
with Holger Wille and Joel Watts (University of California, San
Francisco) and David Westaway (University of Alberta) for this project.
"The prion protein was discovered over twenty years ago and has been
studied intensively. Nobody, however, knew its evolutionary origin and
much confusion surrounds its physiological function," says Prof.
Schmitt-Ulms. The team's analysis suggests that the prion gene is
descended from the more ancient ZIP family of metal ion transporters.
Members of the ZIP protein family are well known for their ability to
transport zinc and other metals across cell membranes.
The U of T laboratory initially demonstrated the physical proximity of
two metal ion transporters, ZIP6 and ZIP10, to mammalian prion proteins
in living cells. As with the normal cellular prion protein, ZIP6 and
ZIP10 exhibit widespread expression in biological tissues with high
transcript levels in the brain. Schmitt-Ulms then made the startling
discovery that prion and ZIP proteins contain extensive stretches of
similar amino acid sequence. The researchers next documented that the
respective segments within ZIP and prion proteins are computationally
predicted to acquire a highly similar three-dimensional structure.
Finally, the team uncovered multiple additional commonalities between
ZIP and prion proteins which led them to conclude these molecules are
evolutionarily related.
Most proteins do not act in isolation but partner with other proteins to
exert their biological roles. The relationship between ZIP-family and
prion proteins may thus provide a new angle from which to study the
biology of the prion protein in health and disease. The level of shared
characteristics between these protein families, in addition to the
presence of prion protein genes in most chordate (i.e., backboned)
species, place the split from the ZIP-like ancestor gene at the base of
the chordate lineage.
Although no single evidence firmly established the phylogenetic
relationship between ZIP and prion genes, Schmitt-Ulms is confident that
the many corroborating pieces of evidence collected and, equally
important, the absence of any conflicting observations, allow no other
conclusion to be drawn.