PACKARD CENTER UPDATE:
From: alscenter@jhmi.edu To: The ALS Community Date: December 20, 2007 Subject: Robert Packard Center ALS News Network

TREATMENT: A MATTER OF CLEANING HOUSE? The rogue's list of what might cause ALS or what events might drive it forward is long - it includes overstimulated motor neurons, overactive immune cells, damage by toxic free radicals and a pulling away of motor neurons from muscle. But one older idea on the list - that the disease arises in part from flawed cell housekeeping - is standing out of late, largely due to a wave of enthusiasm from its proponents. It is, in fact, undergoing what molecular neurogeneticist J. Paul Taylor calls "a renaissance" because the genes that direct this very basic cell process have come to light. And more exciting is new research that suggests at least some housekeeping lapses are correctable, prompting hope for a new therapeutic path. Taylor, with the University of Pennsylvania, became a Center grantee this fall because of his expertise on protein clearance, the proper term for the housekeeping process. He not only brings a familiarity with its biology but he's also skilled in creating animal models that could shed light on the role of protein clearance in disease. WHY "HOUSEKEEPING?" Proteins carry out a cell's main work such as forming structure and catalyzing reactions. It's no surprise, then, says Taylor, that cells have evolved an exquisitely-tuned system to make sure cell proteins are the highest quality possible. Misfolded or damaged proteins don't simply deprive cells of their usual functions; they take on the role of renegade. To use a slightly-forced analogy: it's like joining a street gang: "bad" proteins' very damage makes them sticky and draws them into large, unmanageable masses - aggregates - that threaten cells. How do protein aggregates compromise cells? That's not well-understood. What is clear, however, is the tie between them and neurodegenerative disease. They're a hallmark of Parkinson's and Alzheimer's disease, for example. Aggregates are also common in ALS. And understanding how they're scrubbed from cells or why they persist is one of neuroscience's - and Taylor's - goals. HOW IT WORKSThough cells use several systems to clear abnormal or excess proteins, two of them stand out in disease processes. In the ubiquitin-proteasome system, molecules are tagged for removal by ubiquitin, a small protein. "Ubiquitinated" proteins ultimately are fed into the narrow opening of a cylindrically-shaped enzyme - called a proteasome - and digested. "Proteasomes have their limitations, though," says Taylor. "They're not able to degrade large, complex protein aggregates. That's why there's an alternate mechanism." So a second evolutionarily older system relies on lysosomes - widely-distributed microscopic sacs containing digestive enzymes - and autophagy (auto-PHAGY). In the latter process, cell cast-offs become membrane-enclosed and the lot fuses with a lysosome. "It's amazing to watch in real time," Taylor remarks. Digestion, then, is rapid. And large, undesirable protein aggregates can usually be dispatched in short order. That the autophagy-lysosomal system works overtime in neurodegenerative disease is well-known. But recently, Taylor confirmed that such activity is a protective response, one that enables clearing of specific aggregates. In the disorder spinobulbar muscular atrophy - a motor neuron disease with similarities to ALS - his team showed autophagy and lysosomes at work to remove typical aggregates. A BACKUP SYSTEM: WHERE IT COULD LEADThere's more. Taylor has also discovered that the two housekeeping systems aren't separated, as was long suspected, but appear to have aspects in common. In his study of fruit flies burdened with a flawed ubiquitin/proteosome system, the unwanted proteins still get dissolved. That's because autophagy and lysosomes step up to compensate. And, most important, Taylor described, in a paper in Nature this summer, how a molecule that's an apparent link between the two systems could be turned up to increase the protective removal of toxic proteins. The molecule, abbreviated HDAC6, somehow shifts housekeeping to favor the autophagy system, the cell's best removal service. "There may be safe ways to increase HDAC6," says Taylor, "and they might develop into treatment for a broad array of neurodegenerative diseases, including, quite possibly, ALS