Parkinson's disease is caused by the degeneration of neurons
in the midbrain. The mechanisms leading to the loss of these neurons, however,
are largely unknown. Recent research revealed that about ten per cent of cases
are caused by defects in so-called Parkinson-associated genes. Furthermore,
mitochondria, the cellular powerhouses, seem to play a major role. New results
from researchers at the LMU Munich under the lead of associate professor Dr.
Konstanze Winklhofer and Professor Christian Haass connect both phenomena,
showing that two Parkinson genes maintain the function of mitochondria.
"Diseases like Parkinson's where at least some cases are unambiguously
related to the dysfunction of specific genes offer a promising research
opportunity," explains biochemist Dr. Konstanze Winklhofer "When we
understand the function of these genes, we can learn a lot about the causes of
the disease, its progress and possible new therapies." Professor Wolfgang
Wurst and his group of the Institute for Developmental Genetics at the
Helmholtz Center Munich also contributed to this work. (Journal of Biological
Chemistry, 21 August, 2009)
Four million individuals are estimated to suffer from
Parkinson's disease worldwide. This neurodegenerative disorder is characterized
by rigid muscles, uncontrollable tremor and slowing – or even loss of – voluntary
movements. It is caused by the death of nerve cells in a midbrain area called
substantia nigra. These neurons secrete dopamine, a neurotransmitter involved
in the control of movements. Thus, a loss of dopamine-producing neurons causes
a dysbalance in the regulation of movements.
"Functionally impaired mitochondria have been
recognized to trigger Parkinson's disease already in the early eighties,"
Dr. Konstanze Winklhofer says, an associate professor at the Adolf-Butenandt
Institute of the Ludwig-Maximilians-Universität (LMU) in Munich. At this time
it was discovered by accident that mitochondrial toxins can induce Parkinson's
disease. The relevance of mitochondria to the loss of neurons seems plausible –
after all, mitochondria supply the cells with energy in form of adenosine
triphosphate and play a substantial role in the regulation of cell death.
The scientists' results now combine both observations on a
genetic basis. They found that the Parkinson-associated genes PINK1 and Parkin
functionally interact to maintain mitochondrial function. Loss of Parkin or
PINK1 function impairs the morphology and activity of mitochondria, which then
produce less adenosine triphosphate. "Our results also confirm the high
neuroprotective potential of Parkin", Winklhofer says. "We observed
that Parkin can compensate a loss of PINK1 function, but not the other way
round". Winklhofer and her colleagues have shown earlier that Parkin can
protect neurons under various stress conditions.
Until today, there is no possibility to prevent or cure
Parkinson's disease. All pharmacological approaches are merely symptomatic and
aim at replacing the neurotransmitter dopamine. Insight into the function of
Parkinson-associated genes can help to identify new targets for therapeutic strategies
in order to prevent or halt the loss of dopamine-producing neurons. So far, six
Parkinson-associated genes are known whose functions remain to be elucidated in
detail. In the case of Parkin and PINK1 scientists have made significant steps
forward and now aim at uncovering the molecular mechanisms of their functions.
Citation: "Loss of parkin or PINK1 function increases
DRP1-independent mitochondrial fragmentation" Journal of Biological Chemistry, 21 August 2009. Vol. 284, Issue
34, 22938-22951
Adolf-Butenandt-Institute
of Physiological Chemistry, Molecular Biology and Metabolic Biochemistry
SOURCE: Ludwig-Maximilians-Universität
München