Old 05-12-2009, 05:16 AM #1 (permalink)
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Default First 'Neuroprotective' Gene In Patients With Amyotrophic Lateral Sclerosis Isolated

ScienceDaily (May 11, 2009) — A genetic variant that substantially improves survival of individuals with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, has been indentified by a consortium of researchers led by John Landers, PhD, Associate Professor of Neurology and Robert Brown, MD, DPhil, Chair and Professor of Neurology at the University of Massachusetts Medical School. Discovery of the KIFAP3 gene variant is reported in the Proceedings of the National Academy of Sciences.

"This report is the first to describe genetic factors that determine rate of progression in ALS," said Brown.

ALS is a progressive, neurodegenerative disorder affecting the motor neurons in the central nervous system. As motor neurons die, the brain's ability to send signals to the body's muscles is compromised. This leads to loss of voluntary muscle movement, paralysis and eventually death from respiratory failure. In 1993, a team of researchers led by Dr. Brown discovered the first gene linked to familial ALS, a protein anti-oxidant known as superoxide dismutase, or SOD1. Earlier this year, Dr. Brown and his colleagues discovered a mutation in the FUS/TLS gene which is estimated to account for 5 percent of inherited ALS cases. There are only four genes known, that when mutated, cause familial ALS. The KIFAP3 gene variant is the first to be linked with the rate of progression in ALS.

To isolate the KIFAP3 gene variant, a consortium of researchers from the U.S., Mexico, Israel and Europe examined more than 300,000 genetic variants in over 1,800 people with ALS and nearly 2,200 unaffected controls. The approach is based on the assumption that naturally occurring gene variations can influence both disease susceptibility and the way a disease runs its course once underway. During their search, the consortium detected a beneficial variant of the KIFAP3 gene which was associated with an increase in survival time of 40 to 50 percent.

Because survival with ALS is normally only three to five years, patients with the KIFAP3 gene variant experience a substantial improvement. In fact, the impact of this genetic variant is comparable to the effect of the only drug (Riluzole) now approved for use in the United States. More importantly, this genetic variant may potentially point the way to future drug development efforts.

While it's still unclear how the KIFAP3 gene variant alters the progression of ALS, researchers know that it is involved with a number of cellular processes, including the transport of essential molecules throughout the nerve cell.

"The favourable gene variant decreases levels of a motor protein complex in nerves," said Landers. "This complex transports substances through different parts of nerve cells. If we can understand the biological basis for the beneficial effect in ALS, it will potentially provide a target for the development of new ALS treatments."

Ammar Al-Chalabi, PhD, co-senior author of the study and Professor of Neurology and complex disease genetics at King's College, London added, "Treatments can now be directly designed to exploit the effect of this gene variation."
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Old 05-12-2009, 11:48 AM #2 (permalink)
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Thanks for sharing. I actually (for once) fully understand the information presented, and the potential of the discovery.
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Old 05-12-2009, 12:17 PM #3 (permalink)
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Wow thanks for the post, things a seem to be a happening... Yippee.. Maybe if we all just hold on we will see something amazing.. Thanks for all the effort..
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Old 05-12-2009, 12:35 PM #4 (permalink)
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40 to 50% ! WOW. That is great news to wake up to.

Thanks for posting that.


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Old 05-12-2009, 02:03 PM #5 (permalink)
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Great news!
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Old 05-12-2009, 08:28 PM #6 (permalink)
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hang in there you guys, looks like the Calvary is on its way!
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Old 05-12-2009, 08:31 PM #7 (permalink)
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Sorry to burst your bubble, but it is compared to Rilutec which only offers a few weeks to a few months of increased life. Not very encouraging.

"is comparable to the effect of the only drug (Riluzole) "
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Old 05-12-2009, 08:37 PM #8 (permalink)
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ooh they talked about that on the als.net forum -- apparently this article isn't written very clearly... the MDA release was better at explaining:

Protective' gene increases survival in motor neuron disease
11 May 2009

A gene that significantly influences the survival rate of people living with motor neuron disease (MND) by 14 months has been identified by scientists in an international research collaboration - funded in part by the MND Association.

Led by Prof Ammar Al-Chalabi at the Medical Research Centre for Neurodegeneration Research, King's College London, and Prof Robert Brown at the University of Massachusetts Medical School, the international research team looked at 300,000 genetic variants in 2,359 people with MND and 2,814 unaffected volunteers from six different countries.

The researchers aimed to narrow the search for genes involved in MND by identifying potential ‘hot spots' linked to the disease which could then be carefully searched, letter by letter, for disease related ‘spelling mistakes' in the human genetic code. Using the same methods, the researchers could also search for gene variants that alter the progression of the disease.

It is this latter approach that has thrown up an exciting result, by identifying a ‘protective' gene that extends the life of people diagnosed with MND - the first in the history of MND research.

KIFAP3 gene - extending survival rate

Researchers have identified a genetic variation in the KIFAP3 gene which is important in determining the survival rate for people with MND.

People with two beneficial variants of KIFAP3 lived on average four years while those with only one or none lived on average for two years and eight months.

Significantly, this represents an improvement in survival of nearly 50% or over 14 months for patients with two beneficial variants. Life expectancy for most people with MND is just two to three years. However, the chances of surviving five years improved from about 10% to more than 30% for those carrying the ‘good' variants of KIFAP3.

So far, only one drug called riluzole has been proven to have an impact on extending the life expectancy of people living with the disease. It has been shown to extend life expectancy by a few months.

What this means for MND research

Prof Al-Chalabi said: "Treatments can now be directly designed to exploit the effect of this gene variation. The more usual situation is for genetic risk factors for a disease to be identified rather than survival genes.

"Genetic risk factors are important but they have limited benefit for designing effective treatments because doctors only see people once they are already affected, so treatments need to be aimed at improving survival, not at reducing risk."

The research also has implications for the design of MND clinical trials. It is possible that an excess of people carrying the beneficial survival gene variants in one group in a clinical trial might make it look as if a drug is effective when it is not, or vice versa.

Dr Brian Dickie, director of research development at the MND Association, explained: "This is a significant finding, bearing in mind the speed with which MND can progress in patients.

"Just as there are genetic ‘villains' that can cause or predispose people to disease, so there are undoubtedly ‘hero' genes that help delay the onset of disease or slow its progression.

"This is the first gene to be associated with such a marked protective effect. Undoubtedly, this research will open up potential treatment strategies for the thousands of people living with MND in the UK and throughout the world."

The reasons why certain variants of the KIFAP3 gene can alter disease progression are still unclear. Researchers know that the gene is involved in a number of cellular processes, most notably the transport of essential molecules throughout the nerve cell. This is an area of MND research that has attracted a lot of attention, as disruption of cellular transport appears to occur in the early stages of the disease.

Prof Brown who led the research in the USA said: "This has truly been a multinational collaboration, involving 19 groups from six countries. It illustrates how effectively an international consortium in MND research can help us understand why motor neurons degenerate in this disease. The challenge now is to turn this new knowledge into effective treatments; the KIFAP3 story provides a new target for therapy development."
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Old 05-12-2009, 08:45 PM #9 (permalink)
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I hope the second article was truthful and not exaggerated as this could be a start of something significant!
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Old 05-12-2009, 09:33 PM #10 (permalink)
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This sounds very promising! Thanks for sharing rocmg.
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Old 05-12-2009, 10:06 PM #11 (permalink)
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Has anyone heard of this song? I saw a talk show last week and they had a Mom and her three adult children on it and the mom had someone perform this song for them.
Does anyone know where I could get it or download it ? My Mother in Law died of ALS last December and we are having a memorial service in July and I thought it would be a nice song to play at the service for her children
thx
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Old 05-13-2009, 01:17 AM #12 (permalink)
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I think you're in the wrong section hlarway.

1: Hum Mol Genet. 2009 Mar 1;18(5):942-55. Epub 2008 Dec 16.Click here to read Click here to read Links
Mutant SOD1 impairs axonal transport of choline acetyltransferase and acetylcholine release by sequestering KAP3.
Tateno M, Kato S, Sakurai T, Nukina N, Takahashi R, Araki T.

1Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.

Mutations in the superoxide dismutase 1 (sod1) gene cause familial amyotrophic lateral sclerosis (FALS), likely due to the toxic properties of misfolded mutant SOD1 protein. Here we demonstrated that, starting from the pre-onset stage of FALS, misfolded SOD1 species associates specifically with kinesin-associated protein 3 (KAP3) in the ventral white matter of SOD1(G93A)-transgenic mouse spinal cord. KAP3 is a kinesin-2 subunit responsible for binding to cargos including choline acetyltransferase (ChAT). Motor axons in SOD1(G93A)-Tg mice also showed a reduction in ChAT transport from the pre-onset stage. By employing a novel FALS modeling system using NG108-15 cells, we showed that microtubule-dependent release of acetylcholine was significantly impaired by misfolded SOD1 species. Furthermore, such impairment was able to be normalized by KAP3 overexpression. KAP3 was incorporated into SOD1 aggregates in human FALS cases as well. These results suggest that KAP3 sequestration by misfolded SOD1 species and the resultant inhibition of ChAT transport play a role in the dysfunction of ALS.

Pretty easy to see how a modified form of KAP 3 (same thing as KIFAP3 I believe) could escape protein aggregates and contribute to greater longevity. There are other protein aggregates in ALS besides SOD1. This looks legit but I bet it will take a lot of time and resources to get anything out of it.

I have not been able to track down the actual study searching for the authors. Anybody who finds a citation post it please. Maybe it's not published yet.
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Old 05-13-2009, 01:21 AM #13 (permalink)
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Hey, maybe SOD1 aggregates are actually the end of the story:
: Ann Neurol. 2007 Dec;62(6):553-9.Click here to read Links

Comment in:
Ann Neurol. 2008 Sep;64(3):356-7; author reply 358.
Ann Neurol. 2008 Sep;64(3):357-8; author reply 358.

Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis?
Kabashi E, Valdmanis PN, Dion P, Rouleau GA.

Centre for Excellence in Neuromics, University of Montreal, the Centre Hospitalier de l'Université de Montreal and Ste-Justine Hospital, Montreal, Quebec, Canada.

The identification in 1993 of superoxide dismutase-1 (SOD1) mutations as the cause of 10 to 20% of familial amyotrophic lateral sclerosis cases, which represents 1 to 2% of all amyotrophic lateral sclerosis (ALS) cases, prompted a substantial amount of research into the mechanisms of SOD1-mediated toxicity. Recent experiments have demonstrated that oxidation of wild-type SOD1 leads to its misfolding, causing it to gain many of the same toxic properties as mutant SOD1. In vitro studies of oxidized/misfolded SOD1 and in vivo studies of misfolded SOD1 have indicated that these protein species are selectively toxic to motor neurons, suggesting that oxidized/misfolded SOD1 could lead to ALS even in individuals who do not carry an SOD1 mutation. It has also been reported that glial cells secrete oxidized/misfolded mutant SOD1 to the extracellular environment, where it can trigger the selective death of motor neurons, offering a possible explanation for the noncell autonomous nature of mutant SOD1 toxicity and the rapid progression of disease once the first symptoms develop. Therefore, considering that sporadic (SALS) and familial ALS (FALS) cases are clinically indistinguishable, the toxic properties of mutated SOD1 are similar to that of oxidized/misfolded wild-type SOD1 (wtSOD1), and secreted/extracellular misfolded SOD1 is selectively toxic to motor neurons, we propose that oxidized/misfolded SOD1 is the cause of most forms of classic ALS and should be a prime target for the design of ALS treatments.
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Old 05-13-2009, 08:24 AM #14 (permalink)
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This is promising to say the least. Any announcements on new developments that increase life or that bring us closer to a cure is encouraging.
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Old 05-14-2009, 01:37 AM #15 (permalink)
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Sounds encouraging. I always notice mistakes in ALS articles written by the media, however. First, this article stated that ALS patients normally survive only one to three years. Not generally true. Then they state that the beneficial gene identified could increase life expectancy 40-50%, about the same as Rilutek. The numbers are a little off there--a few months additinonal survival time is a lot less than 50%.

Oh, I noticed the MDA release was posted--a better article. What I really want to know is why some PALS live longer than 5 years, especially 10 years or more (full-time ventilation not withstanding).
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