Berkeley: An intriguing finding in nematode worms suggests that having a little bit
of extra fat may help reduce the risk of developing some
neurodegenerative diseases, such as Huntington’s, Parkinson’s and
Alzheimer’s diseases.What these illnesses have in common is that they’re caused by
abnormal proteins that accummulate in or between brain cells to form
plaques, producing damage that causes mental decline and early death.
Huntington’s disease, for example, is caused by aggregating proteins
inside brain neurons that ultimately lead to motor dysfunction,
personality changes, depression and dementia, usually progressing
rapidly after onset in people’s 40s.
These protein aggregates – called Huntington’s aggregates – have been
linked to problems with the repair system that nerve cells rely on to
fix proteins that fold incorrectly: the cell’s so-called protein folding
response. Misfolded proteins can make other proteins fold incorrectly,
creating a chain reaction of misfolded proteins that form clumps that
the cell can’t deal with.
When University of California, Berkeley, researchers perturbed the
powerhouses of the cell, the mitochondria, in a strain of the nematode C. elegans
that mimics Huntington’s disease, they saw their worms grow fat. They
traced the effect to increased production of a specific type of lipid
that, surprisingly, prevented the formation of aggregate proteins. The
fat, they found, was required to turn on genes that protected the
animals and cells from Huntington’s disease, revealing a new pathway
that could be harnessed to treat the disease.
The same proved true in human cell lines cultured in a dish.
“We found that the worms and human cells were almost completely
protected from the Huntington’s aggregates when we turned on this
response,” said Andrew Dillin, the Thomas and Stacey Siebel
Distinguished Chair in Stem Cell Research in UC Berkeley’s Department of
Molecular and Cell Biology and a Howard Hughes Medical Institute
investigator.
They subsequently treated worms and human cells with Huntington’s
disease with drugs that prevented the cell from sweeping up and storing
the lipid, called ceramide, and saw the same protective effect.
“If we could manipulate this lipid pathway, we could go after
Huntington’s disease, because in our studies the drugs were really
beneficial,” he said. “This is poised to take to the next level.”
Dillin has already begun experiments in mice with Huntington’s
disease to see if the drugs result in a better outcome. He published his
latest findings online Sept. 8 in the journal Cell.
How Huntington’s disease causes wasting
In an accompanying paper in the same issue of Cell, Dillin also
reports that stressing neurons in the brain makes them release a
hormone, serotonin, that sends alert messages throughout the body that
the brain cells are under attack, setting off a similar stress response
in cells far from the brain. In diseases like Huntington’s, mental
decline is also associated with peripheral metabolic defects and muscle
decline.
“The serotonin release dramatically changes the metabolic output of
peripheral cells and the sources they use for fuel, so we think it is
instituting a large-scale metabolic rewiring, maybe to protect the
neurons in the brain,” he said. “If you begin to shut down the periphery
and stop using the limited resources it utilizes, then more of those
resources can be shifted to brain metabolic activity. This might be a
very clever way to try to save the brain by having the body waste away.”
While Dillin discovered the ability of mitochondria to communicate
between different cells and tissues several years ago, the new study
pinpoints serotonin as a primary driver of this metabolic response, he
said.
Dillin noted that drugs that lower levels of serotonin have long been
used to treat depression and other psychiatric manifestations of
neurodegenerative diseases, but the new findings suggest these
medications may have more widespread use in age-related disease than was
previously thought. These findings have broad implications not only for
the potential treatment of neurodegenerative disorders, but for further
understanding the impact of neurological disease on metabolism and
stress responses throughout the body.
Mitochondria key to brain degeneration
Both discoveries came from studies of mitochondria, the powerhouses of
the cell that burn nutrients for energy but also play a key role in
signaling, cell death and growth. Over the past several years,
increasing evidence has associated mitochondrial dysfunctions with aging
and age-onset protein misfolding diseases such as Alzheimer’s,
Parkinson’s and Huntington’s.
Dillin is particularly interested in Huntington’s disease, which is
inherited and strikes people in their 40s and 50s, inevitably leading to
a wasting death. The genetic cause is well-known – expansion of a part
of a gene that produces a protein with too many added glutamine amino
acids. How this glutamine-rich protein leads to symptoms is only
graduatlly being revealed.
While investigating mitochondria in nematodes genetically engineered
to have Huntington’s disease, Dillin and his colleagues discovered that
the abnormal proteins actually aggregate on the mitochondria, and that
this ramps up the protein folding response within the cell, flooding
both the mitochrondria and the cell interior with nearly 100 types of
so-called heat shock proteins to try to fix the misfolded proteins. The
heat-shock proteins act as mitochondrial chaperones to assist in the
import and folding of mitochondrial proteins synthesized outside of
mitochondria.
The researchers were surprised to find that knockdown of one specific
mitochondrial chaperone, mtHSP70, elicited a unique stress response
mediated by fat accumulation, resulting in improved protein folding in
the interior or cytosol of the cell. Drugs that activate this novel
stress response pathway, which they call the mitochondrial-to-cytosolic
stress response, protected both nematodes and cultured human cells with
Huntington´s disease from protein-folding damage.
“Maybe there is a way to use one drug to alter the mitochondrial
signal and another drug to alter the communciation signal from the
brain,” he said. “You would never see these two effects if you were
studying protein folding in a tissue culture dish, because you don’t
have the whole organism, C. elegans, in which you can look at the signals being communicated.”
Co-authors of the fat study include Hyun-Eui Kim, Ana Rodrigues
Grant, Milos Simic, Rebecca Kohnz, Daniel Nomura, Jenni Durieux, Celine
Riera, Melissa Sanchez, Erik Kapernick and Suzanne Wolff at UC Berkeley.
The second study was co-authored by Kristen Berendzen, Jenni Durieux,
Ye Tian, Hyun-eui Kim and Suzanne Wolff of UC Berkeley, in collaboration
with Li-Wa Shao and Ying Liu of Peking University in Beijing.
The studies are supported by the Howard Hughes Medical Institute,
National Institutes of Health, Glenn Foundation for Medical Research,
and Jane Coffin Childs Memorial Fund for Medical Research