Goldilocks was on to something when she preferred everything "just
right." Harvard Medical School researchers have found that when it comes
to the length of mitochondria, the power-producing organelles, applying
the fairy tale's mantra is crucial to the health of a cell. More
specifically, abnormalities in mitochondrial length promote the
development of neurodegenerative diseases such as Alzheimer's.
"There had been a fair amount of interest in mitochondria in
Alzheimer's and tau-related diseases, but causality was unknown," said
Brian DuBoff, first author of the study and a post-doctoral research
fellow at Massachusetts General Hospital.
"Ultimately, a deeper understanding of the relationship between
mitochondrial function and Alzheimer's may guide us to develop more
targeted therapies in the future," said Mel Feany, HMS professor of
pathology at Brigham and Women's Hospital and senior author of the
paper.
The findings will be published online in the August 23 issue of Neuron.
Tau-related diseases are caused when tau, a protein most commonly
found in neurons, malfunctions. Tau binds to microtubules in cells, a
process known as stabilization. This binding is necessary so the
microtubules can help maintain cell structure and aid in intracellular
processes such as transporting molecules. When tau is defective, most
often due to changes introduced during protein synthesis, it can
accumulate in neurofibrillary tangles, one of the primary markers of
Alzheimer's.
In this particular study, conducted in fruit flies with defective tau
protein, DuBoff found that the mitochondria in the brain cells of these
flies were elongated compared with the mitochondria in flies with
normal tau. The elongation, he observed, adversely affected
mitochondrial function.
"Normally, one mitochondrion will split into two, two mitochondria
will join into one, and that's a critical process for the health and
stability of the mitochondria," said DuBoff. "This mitochondrial dynamic
happens continuously in almost all cells. Interruption of this process
leads to cell death, and loss of nerve cells in the brain results in
loss of function -- memory loss and difficulty in comprehension and
coordination." The presence of defective tau, then, interrupts the
functioning of mitochondria and contributes to neurodegeneration.
To further observe how mitochondrial dynamics were affected by the
presence of defective tau, the researchers modified two sets of genes in
human-tau-expressing flies, one that controls how mitochondria divide
and another that guides how they come together. When the expression of
the gene that causes mitochondrial lengthening, or fusion, was
increased, the level of neurodegeneration in the flies increased and the
flies were sicker. Conversely, when the expression of the gene that
causes mitochondrial division, or fission, was increased, the defect
reversed and the flies' condition improved.
The study also showed that, in addition to tau, two other key
proteins influenced the neurodegenerative process: DRP1, which helps in
the fission of mitochondria, and actin, which is essential to
maintaining cell structure and movement. A previous study in Feany's lab
had shown that the presence of defective tau hampers the activity of
actin. With this knowledge, the researchers were able to piece together
the relationship among the three proteins. DRP1 and actin are
interdependent: the regulatory state of actin is essential for DRP1 and
mitochondria to come together, thus preserving mitochondrial dynamics.
But the presence of defective tau harms this relationship, rendering
DRP1 incapable of maintaining mitochondrial dynamics, which ultimately
leads to neurodegeneration.
"We have a good idea now of where the process starts. We know it ends
with neurodegeneration, and with this study, we know some milestones
along the way," said Feany. "But we still have to fill in the gaps and
learn more about DRP1 and its role in this process."
"Many studies begin by looking at a normal biological process and
then finding ways it goes wrong," said DuBoff. "We did the opposite. We
started with the disease model, identified this phenomenon of DRP1 and
mitochondrial dysfunction, and then followed it back to the basic
biological regulation of this process."
The study was supported by the National Institute of Aging and the Ellison Medical Foundation.
Journal Reference:
- Brian DuBoff, Jürgen Götz, Mel B. Feany. Tau Promotes Neurodegeneration via DRP1 Mislocalization In Vivo. Neuron, 2012; 75 (4): 618 DOI: 10.1016/j.neuron.2012.06.026
Courtesy: ScienceDaily
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