The finding suggests a new way to treat rare inherited metabolic disorders such as Niemann-Pick disease and mucolipidosis Type IV, 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 March 13 in the online, multidisciplinary journal Nature Communications.
Image credit: Xiang Wang and Haoxing Xu, University of Michigan.
This microscope image shows many enlarged lysosomes inside a mouse skin cell. Lysosomes are the cell's recycling centers.
"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 medicine."
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 breaks down.
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 normal size.
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 percent 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 and mucolipidosis Type IV 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 trafficking defects.
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 and mucolipidosis Type IV mice to determine if the molecule alleviates symptoms.
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 Niemann-Pick disease.
The first author of the Nature Communications paper is Dongbiao Shen, a graduate student research assistant in the U-M Department of Molecular, Cellular and Developmental Biology.
Other authors, in addition to Xu, are Xiang Wang, Xinran Li, Xiaoli Zhang, Zepeng Yao, Shannon Dibble and Xian-ping Dong of the U-M Department of Molecular, Cellular and Developmental Biology; Ting Yu and Andrew Lieberman of the U-M Medical School's Department of Pathology; and Hollis Showalter of the Vahlteich Medicinal Chemistry Core in the U-M College of Pharmacy's Department of Medicinal Chemistry.
The work was supported by grants from the National Institutes of Health and the ML4 Foundation.
Haoxing Xu: www.mcdb.lsa.umich.edu/faculty_haoxingx.html
U-M Department of Molecular, Cellular and Developmental Biology: www.mcdb.lsa.umich.edu
Jim Erickson | Newswise Science News
Further reports about: > Bird Communication > Cellular > Drug Delivery > Molecular Target > Nature Immunology > Recycling > building block > calcium channel > calcium channels > calcium ions > cell's recycling > degenerative disease > digestive enzymes > lymph node > lysosome > metabolic disorder > mucolipidosis Type IV > neurodegenerative disease > synthetic biology > worn-out cellular components
Solving the efficiency of Gram-negative bacteria
22.03.2019 | Harvard University
Bacteria bide their time when antibiotics attack
22.03.2019 | Rice University
DESY and MPSD scientists create high-order harmonics from solids with controlled polarization states, taking advantage of both crystal symmetry and attosecond electronic dynamics. The newly demonstrated technique might find intriguing applications in petahertz electronics and for spectroscopic studies of novel quantum materials.
The nonlinear process of high-order harmonic generation (HHG) in gases is one of the cornerstones of attosecond science (an attosecond is a billionth of a...
Nano- and microtechnology are promising candidates not only for medical applications such as drug delivery but also for the creation of little robots or flexible integrated sensors. Scientists from the Max Planck Institute for Polymer Research (MPI-P) have created magnetic microparticles, with a newly developed method, that could pave the way for building micro-motors or guiding drugs in the human body to a target, like a tumor. The preparation of such structures as well as their remote-control can be regulated using magnetic fields and therefore can find application in an array of domains.
The magnetic properties of a material control how this material responds to the presence of a magnetic field. Iron oxide is the main component of rust but also...
Due to the special arrangement of its molecules, a new coating made of corn starch is able to repair small scratches by itself through heat: The cross-linking via ring-shaped molecules makes the material mobile, so that it compensates for the scratches and these disappear again.
Superficial micro-scratches on the car body or on other high-gloss surfaces are harmless, but annoying. Especially in the luxury segment such surfaces are...
The Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) in Arizona released its first image of the surface magnetic field of another star. In a paper in the European journal Astronomy & Astrophysics, the PEPSI team presents a Zeeman- Doppler-Image of the surface of the magnetically active star II Pegasi.
A special technique allows astronomers to resolve the surfaces of faraway stars. Those are otherwise only seen as point sources, even in the largest telescopes...
Researchers at Chalmers University of Technology and the University of Gothenburg, Sweden, have proposed a way to create a completely new source of radiation. Ultra-intense light pulses consist of the motion of a single wave and can be described as a tsunami of light. The strong wave can be used to study interactions between matter and light in a unique way. Their research is now published in the scientific journal Physical Review Letters.
"This source of radiation lets us look at reality through a new angle - it is like twisting a mirror and discovering something completely different," says...
11.03.2019 | Event News
01.03.2019 | Event News
28.02.2019 | Event News
22.03.2019 | Life Sciences
22.03.2019 | Life Sciences
22.03.2019 | Information Technology