This microscope image shows many enlarged lysosomes inside a mouse skin cell. Lysosomes are the cell’s recycling centers. Image: Xiang Wang and Haoxing Xu, University of Michigan
A University of Michigan
cell biologist and his colleagues have identified a potential drug that speeds
up trash removal from the cell’s recycling center, the lysosome.
The finding suggests a new
way to treat rare inherited metabolic disorders such as Niemann-Pick disease,
as well as more common neurodegenerative diseases like Alzheimer’s and
Parkinson’s, said Haoxing Xu, who led a U-M team that reported its findings in Nature Communications.
“The implications are
far-reaching,” said Xu, an assistant professor of molecular, cellular, and
developmental biology. “We have introduced a novel concept—a potential
drug to increase clearance of cellular waste—that could have a big impact on
Xu cautioned, however, that
the studies are in the early, basic research stage. Any drug that might result
from the research is years away.
In cells, as in cities,
disposing of garbage and recycling anything that can be reused is an essential
service. In both city and cell, health problems can arise when the process
Inside the trillions of
cells that make up the human body, the job of chopping up and shipping worn-out
cellular components falls to the lysosomes. The lysosomes—there are several
hundred of them in each cell—use a variety of digestive enzymes to disassemble
used-up proteins, fatty materials called lipids, and discarded chunks of cell
membrane, among other things.
Once these materials are
reduced to basic biological building blocks, the cargo is shipped out of the
lysosome to be reassembled elsewhere into new cellular components.
The steady flow of the
materials through and out of the lysosome, called vesicular trafficking, is
essential for the health of the cell and the entire organism. If trafficking
slows or stops, the result is a kind of lysosomal constipation that can cause
or contribute to a variety of diseases, including a group of inherited
metabolic disorders called lipid storage diseases. Niemann-Pick is one of them.
In previous studies, Xu and
his colleagues showed that proper functioning of the lysosome depends, in part,
on the timely flow of calcium ions through tiny, pore-like gateways in the
lysosome’s surface membrane called calcium channels.
If the calcium channels get
blocked, trafficking throughout the lysosome is disrupted and loads of cargo
accumulate to unhealthy levels, swelling the lysosome to several times its
Xu and his colleagues
previously determined that a protein called TRPML1serves as the calcium channel
in lysosomes and that a lipid known as PI(3,5)P2 opens and closes the gates of
the channel. Human mutations in the gene responsible for making TRPML1 cause a
50% to 90% reduction in calcium channel activity.
In their latest work, aided
by a new imaging method used to study calcium-ion release in the lysosome, Xu
and his colleagues show that TRPML1-mediated calcium release is dramatically
reduced in Niemann-Pick disease cells.
More importantly, they
identify a synthetic small molecule, ML-SA1, that mimics the lipid PI(3,5)P2
and can activate the lysosome’s calcium channels, opening the gates and
restoring the outward flow of calcium ions.
When ML-SA1 was introduced
into mouse cells and human Niemann-Pick Type C cells donated by patients, the
increased flow through the lysosome’s calcium channels was sufficient to speed
trafficking and reduce lysosome storage.
Xu and his colleagues
believe it might be possible to use ML-SA1 as a drug to activate lysosome
calcium channels and restore normal lysosome function in lipid storage diseases
like Niemann-Pick. The same approach might also be used to treat Alzheimer’s
disease and Parkinson’s, neurodegenerative diseases that involve lysosome
Such studies might also
provide insights into the aging process, which involves the very slow decline
in the lysosomes’ ability to chop up and recycle worn-out cellular parts.
“The idea is that for
lysosome storage diseases, neurodegenerative diseases and aging, they’re all
caused or worsened by very reduced or slow trafficking in the cellular
recycling center,” Xu said.
Next step? The researchers
hope to administer ML-SA1 to Niemann-Pick mice to determine if the molecule
In Niemann-Pick disease,
harmful quantities of lipids accumulate in the spleen, liver, lungs, bone
marrow, and brain. The disease has four related types. Type A, the most severe,
occurs in early infancy and is characterized by an enlarged liver and spleen,
swollen lymph nodes, and profound brain damage by the age of 6 months. Children
with this type rarely live beyond 18 months. There is currently no cure for
Filed Under: Drug Discovery