A glitch in the ability to move iron around in cells may underlie a
disease known as Type IV mucolipidosis (ML4) and the suite of symptoms=97
mental retardation, poor vision and diminished motor abilities=97that
accompany it, new research at the University of Michigan shows.
The same deficit also may be involved in aging and neurodegenerative
diseases such as Alzheimer's and Parkinson's, says lead author Haoxing
Xu, an assistant professor of molecular, cellular and developmental
biology.
The findings are scheduled to be published online Sept. 14 in the
journal Nature.
An interest in iron trans****t led Xu to investigate ML4, another
symptom of which is iron-deficiency anemia. Perhaps, he and his
collaborators reasoned, impaired iron trans****t could explain both the
anemia and the other problems that go hand-in-hand with ML4, a genetic
disorder that mainly affects Jews of Eastern European background.
Children with ML4 begin showing signs of developmental delay and eye
problems during the first year of life and typically fail to progress
beyond the level of a 15-month-old. Although the disease is rare,
recent discovery of some children with milder forms of the condition
raises the possibility of additional mild, undiagnosed cases.
To explore the possible role of iron trans****t in the disease, Xu's
group focused on a protein called TRPML1. A mutation in the gene that
produces TRPML1 is known to cause ML4, so the protein seemed like a
logical starting point for investigating mechanisms responsible for
the disease, even though TRPML1 had never been shown to be involved in
iron trans****t. The only protein with that distinction was DMT1, which
facilitates iron uptake in the gut and in cells that will become red
blood cells, but not in most other cell types.
"Essentially all cells, including nerve cells and muscle cells, need
iron," Xu said. "We wondered what happens in those cells where DMT1
isn't found, and we thought there must be an unidentified iron
trans****ter protein, possibly TRPML1."
Unfortunately, TRPML1 isn't the easiest protein to study. Instead of
residing in the cell's easily-accessed outer membrane, where many
other proteins nestle, it hides in a tiny, interior pocket called
lysosome. To probe the protein, Xu's group had to modify a technique
known as the patch clamp, in which a micropipette and electrodes are
attached to a cell membrane to record the activity of individual or
multiple proteins that serve as channels for charged particles (ions)
moving in and out of cells. With their modification, which they call
the lysosome patch clamp, Xu's group was able to record TRPML1
activity in the tiny lysosome.
They found that TRPML1 was indeed capable of ferrying iron out of the
lysosome. But was there any evidence that interfering with that
ability might result in ML4 symptoms? To address that question, Xu's
group studied defective TRPML1 proteins bearing the same mutations as
those found in ML4 patients. Mutations associated with severe symptoms
were the least adept at shuttling iron, while those associated with
milder symptoms were more proficient, although still not fully
functional.
Further experiments confirmed that when TRPML1 is defective, iron
becomes trapped in the lysosome. One result of the buildup is
formation of a brownish waste material, lipofuscin, known as the
"aging pigment." In skin cells, lipofuscin is the culprit responsible
for the dreaded liver spots that appear with increasing age, but in
nerve, muscle and other cells, its ac***ulation has more serious
consequences.
"How lipofuscin causes problems in neurons and muscles is not clear,
but it's believed that this is garbage that, in time, compromises the
normal function of the lysosome," Xu said. "And we know the lysosome
is im****tant for all kinds of cell biology, particularly the recycling
of intracellular components, so if it's damaged, the cell is going to
suffer." Indeed, abnormal ac***ulation of lipofuscin is associated
with a range of disorders including Alzheimer's disease, Parkinson's
disease, and macular degeneration (a degenerative disease of the eye)
and also contributes to the aging process.
"In a sense we can think of ML4 as really early onset of aging," Xu
said.
Now that the connections among TRPML1, iron and lipofuscin are coming
into focus, researchers have new avenues to explore for potential
treatments, not only for ML4 but also for more common
neurodegenerative conditions.
"If we can somehow manipulate the lysosome iron level, we probably can
provide a treatment for the patient," Xu said. "We're not far enough
along for those kinds of experiments yet, but now we know enough to
work toward that goal."
Provided by University of Michigan
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