NEWS&ANALYSIS N E U R O D E G E N E R AT I O N
Potential Alzheimer’s Drug Spurs Protein Recycling
CREDIT: G. GRULLÓN/SCIENCE
Neuron
www.sciencemag.org
SCIENCE
VOL 344
Published by AAAS
small molecule boosts the amount of retromer proteins by 50% or more, and reduces levels of human β amyloid by 39% in neurons from mice expressing a mutant APP seen in Alzheimer’s disease. “The new proretromer drug is brilliant. … If you had asked me whether I thought the retromer could be tweaked specifically, I would have guessed no,” Gandy says. “Time (and trials) will tell whether it has true promise as a therapeutic.” Indeed, indiscriminate recycling of molecules in cells could cause side effects—APP isn’t the only cargo retromers carry. The goal of treatment, Small says, is to tweak the system to bring retromer activity back to normal levels, but he admits that such a drug could end up increasing cargo “flow” in normal cells, which could be harmful—no one knows. “These are all incredibly important questions that we’re actively involved with,” Small says. The compound’s success also depends on endosomes being the site of most APP processing. Most studies confirm this, but a few locate β amyloid production in the Golgi apparatus, an organelle that packages proteins for delivery elsewhere (see diagram). If β amyloid is mainly produced there, a pro-retromer drug could exacerbate ß Amyloid Alzheimer’s disease by delivering more APP. A retromer-boosting drug may also work in Parkinson’s disease. In 2011, two papers revealed that rare mutations in a retromer gene cause that neurodegenerative disorder in families. “That was a big surprise to all of us,” says Petsko, who’s moving to Weill Cornell Medical College in New York City, where he’ll try to identify the critical retromer cargo in Parkinson’s neurons. The group is now raising money for further drug discovery and development— they’ve started to give their compound to mice. The retromer team knows the long odds of developing a safe and effective drug for Alzheimer’s disease, let alone for two brain conditions. “Most attempts at therapy fail,” Petsko says. “I can live with that. I couldn’t live with not trying.”
Downloaded from www.sciencemag.org on April 29, 2014
In 2004, veteran structural biologists giving enzymes greater opportunity to genGregory Petsko and Dagmar Ringe were erate β amyloid. (Enlarged endosomes are looking for a way to make an impact on often seen in Alzheimer’s disease.) “You have Alzheimer’s disease. Frustration ensued. “We APP residing for too long in the endosome,” couldn’t see a fresh approach,” Petsko says. Small says. “And so—bam—that’s where the Then, at a meeting in Colorado, they heard enzymes start cleaving.” Scott Small, a young Columbia University In 2004, however, it wasn’t clear if the retneurologist, describe his research probing the romer defect was a cause or consequence of brains of people who had died of the neurode- the brain disorder. Evidence for causality has generative disorder. “Along comes Scott with accumulated over the last decade. Knocka totally new pathway,” involving an obscure ing out one copy of a retromer gene in mice molecular complex called a retromer, Petsko leads to higher β amyloid and to memory defsays. “This really got our attention.” icits, and variants in several retromer-related Their lunch that day with Small set the genes are associated with Alzheimer’s risk. agenda for a decadelong collaboration that “Some of the story remains speculative,” this week unveils, in Nature Chemical Biol- says neurologist Samuel Gandy of the Mount ogy, a potential new drug lead for Alzheim- Sinai School of Medicine in New York City. er’s. By stabilizing the components of ret- “Importantly, nothing has come along that romers, which act like recycling bins in cells, disproves the model.” the compound could slow or stop the implaWhile Small was building the case for retcable spread of a protein fragment called β amyloid, a likely culprit in neuron APP death in Alzheimer’s. Although preliminary—so far the published work has been done only in cells—the new results have nonetheless impressed some veterans of the Alzheimer’s field. Golgi Endosome Golgi Endosome What Small found a decade ago was that in Retromer Retromer the hippocampus, a key brain region for memory processing, one area typically ravaged by Alzheimer’s disease contained less of a key retromer component than a resistant area. The retromer is a linked set of proteins that encloses car- Recycle, don’t trash. Retromers help return APP to goes of cell surface proteins, including the neuron surface, preventing its breakup into toxic β amyloid’s precursor, helping to recycle β amyloid in the endosome. them from the cell interior to the outer membrane (see diagram). romer dysfunction in Alzheimer’s, Petsko, Small’s discovery that retromers are Ringe, and graduate student Vincent Mecozzi, lacking in the precise area of the brain first all at Brandeis University in Waltham, Masaffected by Alzheimer’s disease offered a pos- sachusetts, set out to design a “chaperone” sible solution to one of the condition’s biggest compound that would stabilize the complex puzzles. In the roughly 99% of Alzheimer’s retromer structure and thereby boost overcases that lack a known genetic cause, no one all retromer numbers. Using structural biolknows why β amyloid builds up in the brain. ogy tools, they identified a weak point in the For the fragment to exist, certain enzymes linked retromer proteins where a single commust cleave its parent, amyloid precursor pound might bind them more tightly together, protein (APP). This is thought to happen in thus stabilizing the complex and slowing typan organelle called the endosome. Based on ical degradation in a cell. After several years his brain studies, Small hypothesized that a of work, and somewhat to their own surprise, lack of retromer activity causes more APP they found such a compound. (and other proteins) to linger in endosomes, In cultured hippocampal neurons, the
–KEN GARBER Ken Garber is a writer based in Ann Arbor, Michigan.
25 APRIL 2014
351
Potential Alzheimer’s Drug Spurs Protein Recycling
CREDIT: G. GRULLÓN/SCIENCE
Neuron
www.sciencemag.org
SCIENCE
VOL 344
Published by AAAS
small molecule boosts the amount of retromer proteins by 50% or more, and reduces levels of human β amyloid by 39% in neurons from mice expressing a mutant APP seen in Alzheimer’s disease. “The new proretromer drug is brilliant. … If you had asked me whether I thought the retromer could be tweaked specifically, I would have guessed no,” Gandy says. “Time (and trials) will tell whether it has true promise as a therapeutic.” Indeed, indiscriminate recycling of molecules in cells could cause side effects—APP isn’t the only cargo retromers carry. The goal of treatment, Small says, is to tweak the system to bring retromer activity back to normal levels, but he admits that such a drug could end up increasing cargo “flow” in normal cells, which could be harmful—no one knows. “These are all incredibly important questions that we’re actively involved with,” Small says. The compound’s success also depends on endosomes being the site of most APP processing. Most studies confirm this, but a few locate β amyloid production in the Golgi apparatus, an organelle that packages proteins for delivery elsewhere (see diagram). If β amyloid is mainly produced there, a pro-retromer drug could exacerbate ß Amyloid Alzheimer’s disease by delivering more APP. A retromer-boosting drug may also work in Parkinson’s disease. In 2011, two papers revealed that rare mutations in a retromer gene cause that neurodegenerative disorder in families. “That was a big surprise to all of us,” says Petsko, who’s moving to Weill Cornell Medical College in New York City, where he’ll try to identify the critical retromer cargo in Parkinson’s neurons. The group is now raising money for further drug discovery and development— they’ve started to give their compound to mice. The retromer team knows the long odds of developing a safe and effective drug for Alzheimer’s disease, let alone for two brain conditions. “Most attempts at therapy fail,” Petsko says. “I can live with that. I couldn’t live with not trying.”
Downloaded from www.sciencemag.org on April 29, 2014
In 2004, veteran structural biologists giving enzymes greater opportunity to genGregory Petsko and Dagmar Ringe were erate β amyloid. (Enlarged endosomes are looking for a way to make an impact on often seen in Alzheimer’s disease.) “You have Alzheimer’s disease. Frustration ensued. “We APP residing for too long in the endosome,” couldn’t see a fresh approach,” Petsko says. Small says. “And so—bam—that’s where the Then, at a meeting in Colorado, they heard enzymes start cleaving.” Scott Small, a young Columbia University In 2004, however, it wasn’t clear if the retneurologist, describe his research probing the romer defect was a cause or consequence of brains of people who had died of the neurode- the brain disorder. Evidence for causality has generative disorder. “Along comes Scott with accumulated over the last decade. Knocka totally new pathway,” involving an obscure ing out one copy of a retromer gene in mice molecular complex called a retromer, Petsko leads to higher β amyloid and to memory defsays. “This really got our attention.” icits, and variants in several retromer-related Their lunch that day with Small set the genes are associated with Alzheimer’s risk. agenda for a decadelong collaboration that “Some of the story remains speculative,” this week unveils, in Nature Chemical Biol- says neurologist Samuel Gandy of the Mount ogy, a potential new drug lead for Alzheim- Sinai School of Medicine in New York City. er’s. By stabilizing the components of ret- “Importantly, nothing has come along that romers, which act like recycling bins in cells, disproves the model.” the compound could slow or stop the implaWhile Small was building the case for retcable spread of a protein fragment called β amyloid, a likely culprit in neuron APP death in Alzheimer’s. Although preliminary—so far the published work has been done only in cells—the new results have nonetheless impressed some veterans of the Alzheimer’s field. Golgi Endosome Golgi Endosome What Small found a decade ago was that in Retromer Retromer the hippocampus, a key brain region for memory processing, one area typically ravaged by Alzheimer’s disease contained less of a key retromer component than a resistant area. The retromer is a linked set of proteins that encloses car- Recycle, don’t trash. Retromers help return APP to goes of cell surface proteins, including the neuron surface, preventing its breakup into toxic β amyloid’s precursor, helping to recycle β amyloid in the endosome. them from the cell interior to the outer membrane (see diagram). romer dysfunction in Alzheimer’s, Petsko, Small’s discovery that retromers are Ringe, and graduate student Vincent Mecozzi, lacking in the precise area of the brain first all at Brandeis University in Waltham, Masaffected by Alzheimer’s disease offered a pos- sachusetts, set out to design a “chaperone” sible solution to one of the condition’s biggest compound that would stabilize the complex puzzles. In the roughly 99% of Alzheimer’s retromer structure and thereby boost overcases that lack a known genetic cause, no one all retromer numbers. Using structural biolknows why β amyloid builds up in the brain. ogy tools, they identified a weak point in the For the fragment to exist, certain enzymes linked retromer proteins where a single commust cleave its parent, amyloid precursor pound might bind them more tightly together, protein (APP). This is thought to happen in thus stabilizing the complex and slowing typan organelle called the endosome. Based on ical degradation in a cell. After several years his brain studies, Small hypothesized that a of work, and somewhat to their own surprise, lack of retromer activity causes more APP they found such a compound. (and other proteins) to linger in endosomes, In cultured hippocampal neurons, the
–KEN GARBER Ken Garber is a writer based in Ann Arbor, Michigan.
25 APRIL 2014
351
