A Lesson in Basic Gene Expression

Directions for making proteins are encoded in the DNA sequences of genes, which reside on chromosomes in the nucleus of each cell. But for proteins to be made, a gene’s DNA code must be copied, or transcribed, onto mRNA molecules, which migrate from the nucleus and into the cytoplasm where the cell’s protein-making machinery is located. For as long as it exists, an mRNA molecule can act as a template for making copies of a protein. So scientists have long suspected that cells must have ways for degrading mRNAs when, for example, a protein starts accumulating to harmful levels. “The cell somehow decides to destroy its mRNA on cue, but nobody knew how this happens,” said Dr. Singer. _EinsteinNews

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Understanding gene expression is one of the keys to the discovery of how to live much longer and healthier lives. The basic outline of gene expression has been known for several decades, but the details of control and timing of the complex networks of gene expression are just being exposed.

Scientists at Albert Einstein College of Medicine recently made a basic discovery in the control of messenger RNA lifespan, which may help to unlock one of the important doors to understanding.

When genes are transcribed, a part of the gene called the promoter region has the job of switching on the gene so that DNA will be copied into mRNA. The Einstein scientists found that the promoter regions of the SWI5 and CLB2 genes do something else as well: they recruit a protein called Dbf2p, which jumps onto mRNA molecules as they’re being synthesized.

These mRNAs—transcribed from the SWI5 and CLB2 genes and bearing the Dbf2p protein—make their journey from the nucleus into the cytoplasm. Here a protein called Dbf20p joins Dbf2p aboard the mRNA molecules—and the two proteins together call for the molecules’ precipitous decay.

“Our findings indicate that genes making proteins whose levels must be carefully controlled contain promoter regions that sentence their mRNA molecules to death even as the mRNA is being born,” said Dr. Singer. “The promoter regions do that by ‘marking’ the newly made mRNA with the protein Dbf2p—the common factor between mRNA synthesis and its ultimate decay. Dbf2p stays attached to the mRNA from its birth and then, responding to a signal indicating that no more protein should be made, orders mRNA’s destruction.” _EinsteinNews

You see, as long as the messenger RNA stays around in the cytoplasm, it will keep binding to ribosomes, and continue to produce its protein. This is not what the cell wants, in general, since the relative quantities of different proteins are maintained in a healthy balance.

The application of this discovery to life extension is not immediately apparent to the casual reader. And yet as we come to understand the build-up of imbalances within cells which accompany the ageing process, we are likely to find multiple ways in which this particular system can go wrong, and contribute to degenerative changes.

The better we understand this complex dance of molecules, the better will be our solutions to the problems that occur when the complex system begins to break down. Eventually, we will probably want to re-design some of these sub-systems in ways to make them more robust.

PDF of actual study, published in Cell

Salk Researchers Take a Stab at New Approach to Alzheimer's Tx

At present, there are few drugs that improve the memory deficits associated with normal aging and none that prevent cognitive decline in chronic neurodegenerative conditions such as Alzheimer's disease (AD). Except for the rare cases of familial AD, the cause of AD is not known, but the disease is highly correlated with aging, a process involving a wide variety of physiological changes. Therefore, it is likely that the cells in the aging brain are compromised not from a single cause but from the convergence of multiple insults. However, the currently most widely used approach to drug discovery is to identify a single molecular target and then make a drug that alters this target [1]. Unfortunately, drugs for AD that were developed through this approach have all failed in clinical trials, perhaps because one target is not sufficient or because the targets are also critical for normal brain function so that their inactivation results in toxicity. Therefore, a different approach to drug discovery for AD is needed [2], [3]. _PLoS

Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model. _PLoS

The "amyloid hypothesis" has not been a productive research pathway for finding cures for Alzheimer's -- at least not yet. Salk researchers chose to develop a new series of pharmacological agents based upon the neuroprotective action of the herb curcumin. Curcumin does not enter the brain in high enough concentrations to reverse the symptoms of Alzheimer's Disease, once the disease has progressed to the symptomatic stage. But the new Salk molecules, based upon curcumin's effect, are able to reverse some of the signs of neurodegeneration in aging animal brains.

If the new drug -- J147 -- proves to be effective, and is as safe as curcumin itself, it is likely to become the prototype for a new approach to treating neurodegeneration of aging in general, and Alzheimer's in particular.

H/T Gizmag

Monoclonal Antibody Prophylactic Injection for Alzheimer's Disease

We are learning how to diagnose Alzheimer's disease before it has begun to manifest symptoms. Genomic studies tell us who is most likely to develop the disease, and new lab tests and scanning tools can identify the disease in its earliest stages, before it starts causing apparent problems. But it is not helpful to know that a person is doomed to suffer Alzheimer's unless you have a useful treatment or preventative. Now, such a prophylactic treatment for Alzheimer's is being studied in Britain: Gantenerumab, a monoclonal antibody against amyloid protein.

....gantenerumab, made by Roche, is designed to be given up to four years before the disease has been diagnosed. It is aimed at people with memory problems that have caused them concern but who are still able to go about their day-to-day lives.

It contains an antibody that homes in on amyloid, the toxic protein that clogs the brain in Alzheimer’s, and speeds up its clearance from the body. In small-scale early trials on men and women who already had Alzheimer’s, it cut the amount of amyloid in the brain by up to a third in just six months, the journal Archives of Neurology reports.

It is hoped that giving it earlier would be even more effective and the drug is now being tested on 360 people in 15 countries with mild memory problems that are expected to progress to dementia. To take part in the trial, people must be aged between 50 and 89 and have memory problems that are causing them concern.

A lumbar puncture will confirm that amyloid is building up in their system, although they have yet to be diagnosed with dementia. Those taking part in the Scarlet Road Study trial will be given gantenerumab every month for two years, or a dummy drug.

...Dr Perry, a consultant neurologist at London’s Charing Cross Hospital and at the Re:Cognition Health memory clinic, said: ‘We know that the amyloid is there for many years beforehand and it is thought that if you are going to reduce the amounts to have an effect, we have got to do that before people have significant damage.’

Barbara Sahakian, a professor at Cambridge University’s psychiatry department, said she was ‘thrilled’ by the launch of the trial. She said: ‘The implications are far-reaching.
‘On a personal level, being able to stay at work and maintain your family life and all your hobbies and interests would be just fabulous. ‘There are also great implications for relatives and for society. ‘Institutional care is extremely expensive and if we had effective treatments, we could use that money in a different way.’

Dr Marie Janson of Alzheimer’s Research UK said: ‘Although research into gantenerumab is still in its early phases, initial results have looked promising.’

To find out about joining the trial, visit www.scarletroadstudy.com _DailyMail_via_ImpactLab

Advanced societies around the world are ageing quickly, due to a reduction in birthrates plus lifespans that keep extending due to better food, sanitation, health habits, and health care. As more people reach old age, Alzheimer's disease will become more prevalent. As fewer people are born to support those who age, the disease will become a tremendous societal burden, unless effective treatments can extend a person's lucid lifespan along with the ability to be productive to a later age.