Parkinson's-linked mutation makes neurons
vulnerable to calcium-induced death
A new study reveals the mechanism by which a
genetic mutation linked with Parkinson's
disease (PD) renders dopamine neurons
particularly vulnerable to cell injury and
death.
The research is published by Cell Press in
the March 13th issue of the journal
Molecular Cell.
PD is a neurodegenerative disease
characterized by a specific loss of dopamine
neurons.
Several genes have been linked with
inherited forms of PD.
Many of these genes encode proteins that are
targeted to mitochondria, tiny intracellular
"power plants" that metabolize oxygen and
generate energy.
Mitochondria
also play a major role in maintaining
appropriate calcium levels inside of cells.
Abnormal calcium levels can be toxic to
neurons and are associated with a range of
neurodegenerative diseases.
Mutations in the PINK1 gene cause an
inherited form of PD and research has shown
that PINK1 is localized to mitochondria.
"We previously demonstrated that PINK1
deficiency results in an age related loss of
neuronal viability, and an increased
sensitivity to mitochondrial dysfunction.
However, the mechanisms underlying this
mitochondrial pathophysiology remained
unknown," explains senior study author Dr.
Andrey Y. Abramov from the Institute of
Neurology in London.
Dr. Abramov and colleagues used a
sophisticated and dynamic imaging technique
to explore the mitochondrial pathophysiology
of PINK1-dependent PD. They found that loss
of PINK1 resulted in an aberrant calcium
overload inside the mitochondria.
This overload stimulated production of
dangerous reactive oxygen species that
interfered with the ability of the
mitochondria to transport sugar needed for
energy production. This phenomenon could be
reversed by providing substrates for energy
production.
"These data strongly suggest that the
respiratory complexes in PINK1 deficiency
are still intact and that their functional
inhibition is in fact secondary to reduced
substrate supply," offers Dr. Abramov.
Importantly, adult dopamine-producing
neurons are frequently exposed to large
influxes of calcium that must be buffered by
the mitochondria.
Mitochondria dysfunction and an inability to
process these calcium loads are likely to
make the dopamine neurons quite vulnerable
to injury
"Our findings define a mechanism whereby
PINK1 dysfunction may cause the death of
dopamine neurons," concludes Dr. Abramov.
