New research by University of Michigan cell biologist Haoxing Xu and colleagues reveals key details about how the cell's garbage dump and recycling center, the lysosome, functions. These insights, which may lead to better understanding of conditions such as amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) and Charcot-Marie-Tooth (CMT) disease, suggest new avenues of treatment for these and other diseases that cause nerves and muscles to malfunction.
The research, published this week in the online, multidisciplinary journal Nature Communications, focused on gateways called calcium channels in the lysosome membrane. Calcium channels, which also are found in the membranes surrounding muscle and nerve cells, are made of proteins that respond to signals in the form of electrical impulses. When the proper signal comes along, the proteins open the channel, allowing calcium to pass through. The calcium, in turn, triggers some vital process such as muscle contraction or the release of a hormone or neurotransmitter (a chemical messenger involved in nerve transmission).
Scientists know a lot about the workings of calcium channels in the surfaces of muscle and nerve cells, but understanding what goes in the lysosome---a tiny pouch hidden inside the cell---has been a challenge, said Xu. Consequently, the exact identity of the protein involved and how it becomes activated have remained a mystery.
To explore the channel and its workings, Xu's group modified a technique known as the patch clamp, in which a scaled-down pipette and electrodes are attached to a cell membrane to record the activity of one or more proteins making up the channel. With their modification, which they call the lysosome patch clamp, the researchers determined that a protein called TRPML1 serves as the calcium channel in lysosomes and that a lipid known as PI(3,5)P2 carries the signal that activates the protein.
This particular protein and lipid aren't obscure characters previously unknown to science. A mutation in the gene that produces TRPML1 is known to cause Type IV mucolipidosis (ML4), a genetic disorder that affects mainly Jews of Eastern European background and results in mental retardation, poor vision and diminished motor abilities. And mutations in the enzymes needed to make PI(3,5) P2 cause a variety of neurodegenerative diseases including ALS and CMT.
The protein TRPML1 also is of interest because of the unusual way it does its work.
"While other channel proteins are in the 'passenger' seats of the membrane traffic, TRPML1 is in the 'driver' seat," said Xu, an assistant professor of molecular, cellular and developmental biology. This suggests that manipulating TRPML1 channel activity using channel activators or inhibitors could affect membrane traffic.
"If you can activate the channel, it might be possible to overcome the membrane traffic defects caused by the disease-causing mutations. Luckily, small-molecule chemicals that can stimulate TRPML1 channel activity are already available, " Xu said.
He and collaborator Miriam Meisler, a human genetics professor at the U-M Medical School, have experiments underway to see if they can prevent or reverse the course of disease in a mouse model of ALS by increasing activity of the TRPML1 channel.
If the strategy is successful, Xu hopes to explore its use in treating other neurological diseases.
"If the system we're studying turns out to be compromised in more common diseases, the method of increasing channel activity could have important implications for their treatment," he said.
Xu's coauthors on the Nature Communications paper are postdoctoral fellows Xian-ping Dong, Xiping Cheng and Yanling Zhang; graduate students Dongbiao Shen, Xiang Wang, and Qi Zhang; and undergraduate students Taylor Dawson and Xinran Li, all at U-M; Lois Weisman, who is the Sarah Winans Newman Collegiate Professor in the Life Sciences at U-M; and Markus Delling of Children's Hospital Boston.
The research was funded by the U-M Department of Molecular, Cellular & Developmental Biology; the U-M Biological Sciences Scholars Program; the U-M Initiative on Rare Disease Research, the Michigan Alzheimer's Disease Research Center, the National Multiple Sclerosis Society and the National Institutes of Health.
Haoxing Xu: http://www.mcdb.lsa.umich.edu/faculty_haoxingx.html
Nature Communications: http://www.nature.com/ncomms/index.html
Nancy Ross-Flanigan | Newswise Science News
Further reports about: > Amyotrophic lateral sclerosis > Bird Communication > CMT > Cell's Recycling Center > Charcot-Marie-Tooth > Disease > Lou Gehrig's Disease > Neurotransmitter > Recycling > Science TV > TRPML1 > calcium channel > degenerative disease > nerve cell > neurodegenerative disease > neurological disease
Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University
How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung
Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.
Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....
Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.
The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
26.05.2017 | Life Sciences
26.05.2017 | Life Sciences
26.05.2017 | Physics and Astronomy