June 7, 2017
Credit: Juntendo University
Investigations by scientists in Japan illustrate
how the loss of a key mitochondrial protein facilitates the progression of
Parkinson's disease. The findings are published in Nature
Communications (June 2017).
There is much evidence to suggest that dysfunction within cellular
components contributes to the development and progression of the
neurodegenerative disorder Parkinson's disease. However, exactly how individual
genes and proteins contribute to the degradation of this integral cellular
structure is unclear.
Mitochondria are sub-units within cells that control biochemical
processes such as energy production. They have a double-membrane structure, the
inner membrane of which forms multiple layers or 'cristae.' Each crista
structure must remain intact in order for the mitochondria to perform their
tasks effectively.
Now, Hongrui Meng and Chikara Yamashita at Juntendo University
Graduate School of Medicine in Tokyo, and co-workers across Japan, have shown
how a mitochondrial protein called CHCHD2 plays a key role in
maintaining cristae structure and mitochondria integrity.
Meng and Yamashita's team generated CHCHD2 mutant fruit flies
(Drosophila), and examined what happened when CHCHD2 protein expression was
lost. They found that this loss resulted in abnormal matrix structures and
impairments to oxygen respiration in mitochondria. This in turn led to neuron
loss through oxidative stress, and also to motor dysfunction – such as loss of
climbing ability—as the flies aged.
When the researchers introduced a wild-type form of human CHCHD2
and a metabolic regulator 4E-BP to the flies, the dysfunctions were reversed.
Further investigations showed that CHCHD2 binds to a mitochondrial protein
cytochrome c along with a cell death regulator MICS-1. This binding helps cells
to function properly and ensure correct cell death signaling in both mammalian
cells and Drosophila.
As the team states in their paper published in Nature Communications, their
results shed light on the role of CHCHD2 mutations in Parkinson's disease and
offer "potential therapeutic targets in Parkinson's caused by
mitochondrial dysfunction."
Background
The recent discovery of a gene related to Parkinson's disease,
CHCHD2, is allowing scientists to directly investigate the molecular details
behind the disorder in more depth. The gene encodes a protein, CHCHD2, the role
of which Hongrui Meng and his team in Japan aimed to investigate using fruit
fly and mouse models.
The mutant fruit flies lacked the CHCHD2 protein, resulting in
flies with shorter life spans and problems with motor function as they aged.
The loss of the protein resulted in the integral structure of the flies'
mitochondria was disrupted. The researchers also discovered that by affecting
the oxygen respiration processes within mitochondria, the loss of CHCHD2
generates excess reactive oxygen species in the body. This in turn exacerbates oxidative stress and
directly affects the function and survival of neurons in the body. Importantly,
these phenotypes were not rescued by the reintroduction of CHCHD2 missense
mutants associated with Parkinson's disease, strongly suggesting that this
disease develops by the loss of CHCHD2 function.
Implications of the current study
These findings suggest that CHCHD2 is a key protein that regulates
the mitochondrial respiratory function through stabilizing cytochrome c.
Without it, through mutations in the CHCHD2 gene, mitochondria cannot function
correctly, leading to the progression of Parkinson's disease. The researchers
believe their insights into the gene, its associated protein, and how the protein works to facilitate healthy
functioning of mitochondria could inform future therapies for
Parkinson's disease and help scientists better understand the condition.
More information: Loss of Parkinson's disease-associated protein CHCHD2 affects
crista structure and destabilizes cytochrome c. Nature
Communications DOI:
10.1038/ncomms15500
Provided by: Juntendo
University
https://medicalxpress.com/news/2017-06-potential-therapeutic-parkinson-disease.html
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