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. 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（溶酶体） , functions. These insights, which may lead to better understanding of conditions such as amyotrophic lateral¹ sclerosis (ALS肌萎缩性脊髓侧索硬化症, 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 malfunction²（故障，失灵） .

The research, published this week in the online, multidisciplinary（有关各种学问的） journal Nature Communications, focused on gateways³ called calcium⁴ channels in the lysosome membrane⁵. Calcium channels, which also are found in the membranes⁶ 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 contraction⁷ or the release of a hormone⁸ or neurotransmitter（神经递质） (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 pouch⁹（小袋） hidden inside the cell---has been a challenge, said Xu. Consequently, the exact identity of the protein involved and how it becomes activated¹¹ 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（移液管） and electrodes are attached to a cell membrane to record the activity of one or more proteins making up the channel. With their modification¹², which they call the lysosome patch clamp, the researchers determined¹³ 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 activates¹⁴ the protein.

This particular protein and lipid（油脂） aren't obscure characters previously¹⁵ unknown to science. A mutation¹⁶ in the gene¹⁷ that produces TRPML1 is known to cause Type IV mucolipidosis (ML4), a genetic¹⁸ disorder¹⁹ that affects mainly Jews of Eastern European background and results in mental retardation²⁰, poor vision and diminished motor abilities. And mutations in the enzymes²¹ 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 molecular²², cellular²³ and developmental biology. This suggests that manipulating TRPML1 channel activity using channel activators or inhibitors could affect membrane traffic.

"If you can activate¹⁰ the channel, it might be possible to overcome the membrane traffic defects caused by the disease-causing mutations. Luckily, small-molecule chemicals that can stimulate²⁴ TRPML1 channel activity are already available, " Xu said.

He and collaborator²⁵ 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（神经学上的） 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.