Gene Linked to Alzheimer's Disease Plays Key Role in Cell Survival
Scientists have discovered that a gene linked to Alzheimer's disease may play a beneficial role in cell survival by enabling neurons to clear away toxic proteins. A study funded by the National Institute on Aging (NIA), part of the National Institutes of Health, shows the presenilin 1 (PS1) gene is essential to the function of lysosomes, the cell component that digests and recycles unwanted proteins. However, mutations in the PS1 gene—a known risk factor for a rare, early onset form of Alzheimer's disease—disrupt this crucial process.
Hamidi: For more than a decade, researchers have known that two particular genes: presenilin 1 and 2 play an important role in the development of Early-onset Alzheimer’s disease. A new study, funded by the National Institute on Aging and published recently in the journal Cell by Dr. Ralph Nixon and colleagues, demonstrates a newfound role of presenilin proteins. Dr. Lorenzo Refolo, program director at National Institute on Aging in the division of Neuroscience and Dementias of Aging Branch, explains the findings.
Dr. Refolo: What's new here is that Dr. Nixon and his group found that the presenilin proteins one of it's normal roles is to somehow regulate this endosomal-lysosomal autophagy system by creating the right kind of environment within the system to start degrading proteins—both normal proteins and toxic proteins. Nobody had any clue that this was a function of presenilin.
Hamidi: This newly discovered function of presenilin works as a type of housekeeping mechanism—removing unwanted and potentially toxic proteins from the cell. Scientists refer to this process as macroautophagy.
Dr. Refolo: Sometimes, cells produce more proteins than are actually needed and these proteins need to be cleared from the cell because if they accumulate they can lead to some unwanted sort of side effects, if you would. This is an organelle system, which is responsible for removing those proteins.
Hamidi: What makes a protein toxic? Dr. Refolo explains that this is not entirely understood. However, one thing that is known is that structure plays an important role. Sometimes proteins take on a particular shape referred to as a beta-pleated sheat. This structure, says Dr. Refolo, increases the probability of proteins clumping together in the cell, leading the cellular toxicity which as been implicated in alzheimer's disease.
Dr. Refolo: Somehow, this structure, as these proteins accumulate in the cell, give signals to cells, in the case of alzheimer's disease, to neurons that things are not going well and that the neurons start a degenerative process. Often what happens is that these toxic proteins not only accumulate in the cell itsef, but get outside of the cell so they're found extra-cellularly and this is also very bad because then they can affect not only the cell that's producing them but the cells surrounding that cell and it’s almost like a domino effect and these proteins get out sort of get loose and do their bad, dirty work in the brain.
Hamidi: In other words, mutations in the presenilin gene are unfavorable because (1) it leads to an increase in the ABeta peptides and (2) the mutations disable the cell’s housekeeping machinery from working properly, thereby increasing the amount of toxic proteins in the brain.
Dr. Refolo: It's bound to have some therapeutic implications and will probably give more encouragement to the pharmaceutical companies to pursue this drug target. But I think there's some more basic science that needs to be worked out. Again, what’s the signaling mechanism? Are any of the signaling macromolecules are they also drug targets for therapeutics? So it has very broad therapeutic implications.
Hamidi: For more information regarding the study visit www.nia.nih.gov. This is Anahita Hamidi, National Institutes of Health, Bethesda, Maryland.
About This Audio Report
Reporter: Anahita Hamidi
Sound Bite: Dr. Lorenzo Refolo
Topic: Alzheimer’s Gene, Alzheimer’s disease
Additional Info: Gene Linked to Alzheimer's Disease Plays Key Role in Cell Survival