The Lewy
body inclusions are formed mainly through the accumulation of a protein,
called alpha-synuclein. Because of a correlation between the extent of
Lewy body clumps and the severity of the Parkinson's clinical symptoms,
it has been largely accepted that these inclusions accelerate the
disease process. Therefore, identifying molecules and conditions which
decrease or halt the formation of alpha-synuclein-containing toxic
inclusions may be beneficial for Parkinson's disease patients.
A research team led by Assia Shisheva, Ph.D., professor of
physiology in Wayne State University's School of Medicine, has made
breakthrough advancements on a new molecular mechanism that may provide a
means to "melt" these pathological clumps.
For nearly 15 years, Shisheva's laboratory has studied the cellular
functions of two enzymes, PIKfyve and Sac3, and one accessory protein
ArPIKfyve - the three proteins originally discovered by her group from
1999 to 2007 - and the role these proteins play in disease mechanisms.
Previous work by Shisheva's team revealed that if the Sac3 enzyme is not
bound and protected by ArPIKfyve, it is prone to a quick demise inside
the cell. In addition, they found that this double ArPIKfyve-Sac3
protein complex is a part of a bigger, triple assembly incorporating the
PIKfyve enzyme as well. The triple complex controls the production and
turnover of one rare phospholipid molecule that controls the traffic of
membranes towards the digestive system of the cell.
It has remained a mystery why the Sac3 mutations are associated with
neurodegeneration in humans, whereas the human mutations in PIKfyve are
currently linked only to a relatively benign disease of the cornea.
This led Shisheva's team to believe that the double ArPIKfyve-Sac3
complex has separate functions in the brain. Shisheva's group sought to
identify brain-specific proteins that physically interact only with the
double complex ArPIKfyve-Sac3.
In a recent paper, "The protein complex of neurodegeneration-related
phosphoinositide phosphatase Sac3 and ArPIKfyve binds the
Lewy-body-associated Synphilin-1 preventing its aggregation," published
online in the
Journal of Biological Chemistry, Shisheva and her research team characterized a novel interaction partner of the ArPIKfyve-Sac3 complex in the brain. The
Journal of Biological Chemistry is the world's largest and most cited journal based on PageRank algorithm.
"We uncovered that the ArPIKfyve-Sac3 complex binds Synphilin-1, a
protein already implicated in the pathogenesis of Parkinson's disease
through its interaction with alpha-synuclein," said Shisheva. "As
alpha-synuclein, Synphilin-1 is also entrapped in the abnormal Lewy body
deposits. Our study revealed that the ArPIKfyve-Sac3 complex is an
effective inhibitor of aggregate formation by Synphilin-1."
In addition, Shisheva's team found that excessive levels of Sac3
cause protein self-aggregation and further facilitate the clumping by
Synphilin-1. Not surprisingly, researchers in Japan have recently found
that excessive Sac3 accumulates in Lewy bodies. Therefore, the
ArPIKfyve-Sac3 complex may precipitate Parkinson's disease manifestation
in two ways: when it is too low and when Sac3 is disproportionally
high. These observations raise the possibility that increasing the
levels of the ArPIKfyve-Sac3 complex may have a beneficial effect in
Parkinson's disease.
According to Shisheva, the ArPIKfyve-Sac3 complex could shift
Synphilin-1 distribution from a form of multiple aggregates towards the
soluble form. Future attempts to block aggregate formation or to break
down formed aggregates of Synphilin-1 and, possibly, of alpha-synuclein,
based on the ArPIKfyve-Sac3 complex may prove beneficial as a
therapeutic approach in reducing neurodegeneration in Parkinson's
disease.
Source: Eurekalert
