Assaultrocytes

In my post Prion, Garth! I had talked about mutant or misfolded SOD1 (mSOD1) spreading like a prion and infecting neighboring cells. A recently released study from Johns Hopkins shows for the first time in vivo that astrocytes expressing mutant mSOD1 damage the motor neurons they are supposed to protect. In the study, the authors transplanted SOD1G93A glial-restricted precursor cells—glial progenitors capable of differentiating into astrocytes—into the cervical spinal cord of rats to reveal how mutant astrocytes influence WT motor neurons and other cells types (microglia and astrocytes) in an in vivo setting. The G93A mutation of SOD1 is the most studied version of that particular genetic mutation responsible for many inherited (or familial) ALS cases.

This is the strongest evidence to date that "assaultrocytes" are primary culprits in ALS. It also further suggests that even some sporadic ALS can be caused by misfolded SOD1 which escapes proteasomal degradation and gets into the extracellular space. It also suggests that targeting mSOD1 and stem cell implantation of astrocytes can be viable treatment methods.

EDIT: Here is a more in-depth article by Amber Dance at the ALZ Forum.

Headlines

First off, there is some wonderful news: Diaphragm pacing system receives FDA approval for use with ALS patients. This is a device which extends time until vent by electrically stimulating the diaphragm. Note that this will not replace a vent as the diaphragm muscle needs neurons to release acetylcholine to the muscle fibers in order for them to contract. However, I urge all PALS reading this to immediately begin talking with your neurologist about whether this would be right for you. Here is some good information regarding the DPS.

Next up is the recent news regarding the Neuralstem trial involving stem cells implanted in the spines of PALS. Readers can see a poster-style synopsis of current trial data here. The initial results are encouraging, and one patient has even shown improvement. The next step in the trial is cervical implantation where the cells will have the chance to impact the phrenic nerve (the "money" nerve that serves the diaphragm and breathing). There is still much to learn about this technique before it is available to but a few. Remember that this is still a safety trial. I would urge readers to consider the words of Neuralstem's CEO.

Prion, Garth

in a previous post, I had discussed the possibility of misfolded SOD1 aggregating with TDP43 resulting in depletion of TDP43 from the nucleus which caused disruption of cellular processes and cell death. Further, misfolded SOD1 induces glial activation seen in ALS which poisons otherwise healthy neurons. A new study explores the mechanism behind this prion-like behavior, and further indicates that extracellular misfolded SOD1 can be a cause of even sporadic ALS. It also points to a molecular target which could halt progression cold. The study was done at the Brain Research Centre based at the University of British Columbia and the Vancouver Coastal Health Research Institute, in collaboration with researchers at the University of Alberta. The research was supported in part by Amorfix Life Sciences which has a "vaccine" against misfolded SOD1 already in development.

Now Is The Time

I am a huge believer in staying at home while living with ALS, having done so for 4 years now. However, the financial stress is outrageous. I am personally bankrupt and have critically stressed the finances of my family. This is because there are no institutions which would accept me on a vent. Steve Saling, an architect with ALS, proactively designed a residence for people with advanced ALS and MS which utilizes technology to maximize their remaining independence and comfort. Steve currently resides there happily, and last year another PALS on a vent was rescued from a horrific institution and is now safely and happily living there. If I had a Saling Residence anywhere in this state I would have gone to live there instead. Please read the email message below. Immediate Attention - If you've ever wanted to help, here's your chance. Please spread this to anyone and everyone you can. Please write your letters ASAP. See video here for inspiration: http://www.youtube.com/watch?v=KlQvcw3kQe4 We need your help in establishing a residential living center for those suffering from ALS or MS in Georgia - We need your letter no matter where you are, if we can provide a residence like this here, your state could be next! We really need your help in generating the information requested below no later than September 15th. Forward this email to anyone you think can help. If we are unable to make a persuasive case for this facility it will not be approved and Georgia families (and everywhere) will be left to fend for themselves in supporting their loved ones afflicted with ALS/MS. Thanks for your continued support. Bill Saling Immediate Attention- We need your help in establishing a residential living center for those suffering from ALS or MS in Georgia We are in the final stages of securing approval from the State of Georgia to build a skilled nursing facility that will focus on serving residents with neurological diseases or impairments to include an emphasis on providing care to MS and ALS residents. This state of the art facility will utilize technology to provide the maximum personal independence for each resident. All of the necessary paperwork has been submitted and we are now being asked to provide additional written documentation by September 15, 2011 on the challenges currently being faced by those suffering from these illnesses. We need letters from individuals and families outlining the difficulty they have had in securing residential skilled nursing care for patients with ALS or MS. We need letters from doctors and case workers showing the difficulty families have in Georgia trying to find suitable living accommodations for those living with ALS or MS. We need to hear from families who have had to go outside Georgia to find suitable care for their loved ones suffering from ALS or MS. It would be very helpful to hear from healthcare providers on the difficulties they face in finding suitable housing options for people living on a vent. If we cannot convince the State of Georgia there is a pressing need for this type nursing center which is currently not being met by traditional nursing centers, it will not be approved. Any letters of support, documentation or testimony should be addressed to: Division of Health Planning, Department of Community Health Please EMAIL me your letter as soon as possible. I need to receive them before September 15th, 2011, via my email at kherron@sas-ga.org - Please copy Bill Saling at b.saling@yahoo.com

Often Awesome

Today the ALS Community lost yet another member. Tim LaFollette, Mr. Often Awesome, has returned Home. My heart is with his wife Kaylan. While I initially hid my condition for over a year, Tim had the foresight and steel balls to create the Often Awesome video documentary series so that the entire world can see his decline as he battled this disease from start to finish. This is "Tuesdays With Morrie" on steroids -- a very intimate and detailed look into the horror and hope that is ALS. Not only did it show the effect on a young man cut down in the beginning of his prime, but it showed the devastating effect on family, friends, and community. One person may carry the disease, but many suffer irreversible collateral damage. People have told me how brave I am. However, compared to Tim, I merely dabble in ALS. He had the A4V inherited version, the worst and most aggressive possible. Whenever I would feel down about my situation, I would think about Tim and how he dealt with even worse with a fortitude and grace I cannot contemplate. I would like to thank him for unknowingly lending me some of his strength. I never met Tim personally, only having worked with him over Facebook on awareness and advocacy projects. When I heard the news this morning I shed exactly one tear. I then decided to more properly honor his memory by continuing to live with ALS as he did, on my own terms. I also intend to honor Tim by winning my battle and, like he did, help others win theirs. Fuck ALS.

Common Cause?

A sensational bit of news has begun spreading across the ALS Community: A common cause for all forms of ALS has been found!

But has it? Certainly it is a common process but is it really the cause?

The process involved is autophagy. One of the important jobs of autophagy is to break down and recycle misfolded (improperly constructed) proteins marked by another protein called ubiquitin. A proteasome then breaks down the protein into amino acids which are then used to build new proteins It's like tearing a house apart, timber by timber, and reconstructing another from the material. If this process is interrupted or incomplete then you have a pile of junk left laying around which is thought to impede the efficient operation of the cell. An example of this is the amyloid plaques that are thought to cause Alzheimer's. However, removal of those plaques did not affect disease progression.

ALS is now strongly considered to be a "non-cell-autonomous" disease. This means that something outside the cell is causing the disease. Some of the most persuasive evidence for this is a recent study involving cells known as astrocytes become toxic to the motor neurons. This happens in both the inherited form (familial or FALS) and the more common sporadic form (SALS). Previous readers will know about my interest in current research regarding neuroinflammation as a primary cause of ALS and other neurodegenerative disease. This is also a common cause from a variety of triggers. It is, however, upstream of the "cause" identified in the recent news.

The calcium influx from the excitotoxicity created by neuroinflammation damages the mitochondria. In fact, this is a primary event. It is known that the motor neurons "die-back" along the axon, and that mitochondria motility down the axon is one of the first problems in ALS and neuroinflammation models. Once the mitochondria are damaged and cannot be repaired/replaced, pretty much all bets are off inside the cell. The cell becomes starved for energy, the cellular machinery (such as proteasomes) begins to fail, and the mitochondria start producing apoptotic factors which leads to cell death. Normally this wouldn't be a problem as many of the cells in the human body die and are simply replaced (even brain cells). However, the motor neurons you are born with are the very same motor neurons you die with.

I therefore posit that this "common cause of ALS" is too downstream of the actual cause for treatment based solely on it to be effective in and of itself. It's like trying to stop a waterfall at the edge of the cliff rather than building a dam in the stream a mile further behind. I do believe that although this may not lead directly to a single effective treatment, it would nearly certainly be an important part of a "cocktail therapy". The major positive I take away from this is that it answers the question whether the SOD1 model is applicable to all forms of ALS.

Chatterbug

Since I lost the ability to travel and talk, I use Instant Messaging to keep in touch with family and friends all over the world. Everybody seems to have their favorite client, be it MSN, Yahoo, AIM, or Google. Rather than try to force everyone to switch to a client program of my choosing, I installed all of the various programs and created accounts (I did force some to stop using Facebook chat because it doesn't play nicely with my system). This was fine and dandy, but now my boot load time was obnoxiously long and my computer's RAM was getting low, leading to performance issues. Luckily I had bumped my system up to 4GB in anticipation of my higher-than-normal demands. This led me to search for an alternative, where I could combine most or all of my clients into one ("One client to rule them all, one client to find them..."). Prior to disease, most all my computer systems in the house ran Linux. On my personal laptop I used a program called Pidgin which talked to all the major IM services. The Windows port I found a little lacking and probably not a great fit for most users. A friend then suggested Trillian. I installed it, ran through the setup to fill in the login information for my various IM accounts, and launched the application. I was impressed with the sleek interface. All chat sessions are in one tabbed window. The settings are easy to use and customize. And my RAM usage dropped by about half a GB! Trillian doesn't support all of the functionality of the native clients such as video/audio chat and sometimes the file transfer isn't available, but for regular text chat (including the overly-cute emoticons) it works great. If I need the other functions I just pop up the native client and close it when I'm done. To save boot time and RAM I disabled the natives from loading at boot. It also supports a Facebook connection but I found the newsfeed to be annoying; I prefer to leave Facebook on the web browser where it belongs. I would also caution about security: Your IM logins and conversations are not encrypted or secure and possibly subject to inspection by 3rd parties (also quite possible on the natives), so be aware that transmitting sensitive information over this is not advised. If you are a chatterbug like me, I recommend using Trillian on your AAC computer. I would even recommend it for non-disabled people.