"KIF5A Gene Associated with the Development of ALS"

An international research team has identified a new gene, KIF5A, that they say is associated with the development of amyotrophic lateral sclerosis (ALS) which is also known as Lou Gehrig's Disease. ALS is a neuro-degenerative disease that over time, breaks down a person's ability to control or initiate muscle movement, in most cases leading to paralysis and death withing 2-5 years of diagnosis. It is caused by the breaking down of neurons in both the brain and spinal cord and about 10% of diagnosed patients are classified as "genetic" or "familial" in nature and caused by genetic defects while the other 90% are "sporadic" or without a direct family history.

According to the article this discovery will help advance the understanding of ALS and helps point a finger at the cytoskeleton as a focal point for potential new drug development. The cytoskeleton is the structure that makes up the axon which transfers electrical impulses and information through proteins. The cytoskeleton is where defects that are associated with or cause the effects of ALS can be found. KIF5A's job is to move signals up and down the cytoskelton within the axon, without KIF5A functioning properly, this important information is not able to be transferred. In addition to this KIF5A also plays an important role in mediating RNA transfer, and RNA processing also happens to be considered as a pathogenesis to ALS. This gene was discovered to be associated with ALS through 2 different, successful approaches which were financially supported by multiple organizations including the ALS Association.

Patients with this particular gene mutation are expect to live, on average, 10 years post diagnosis which is much longer than the average ALS patient. This information alone is huge for patients who wish to identify how much time they have. As someone who is dealing with my former coach/mentor/father figure's ALS diagnosis just over a year ago, and his subsequent physical struggles since, this is a small addition of hope that A) may lead to more useful research and information in the diagnosis and treatment of ALS and B) may allow him (if he chooses to) to be tested for this genetic defect to give some indication or forecast of how quickly this disease will affect him. One of the toughest parts of dealing with a loved one's ALS diagnosis is the uncertainty of how quickly the disease progresses. A guy that I went to grade school with passed away 4-5 years ago only 6 months after his diagnosis while in his early 20s, while we have seen in the case of Stephen Hawking, though rare, some people are able to survive a very long time with this disease. When you know your time left to see someone you care about is short, but you don't know how short, it can lead to tough decisions to be made for both the diagnosed and their loved ones. Having this first hand knowledge makes me think that this discovery is huge for ALS patients and their families and I am so hopeful for what may come next.



Link-
https://www.drugtargetreview.com/news/30715/kif5a-gene-als/

Additional link-
https://medicalxpress.com/news/2018-03-als-gene-common-role-cytoskeleton.html

Journal post of the study-
http://www.cell.com/neuron/fulltext/S0896-6273(18)30148-X

The Fruits of the Ice Bucket Challenge and A.L.S

          Were you one of the 17 million people who partook in the famous Ice Bucket challenge? Well if you did, you should be glad to know that you helped to raise not only awareness for Amyotrophic Lateral Sclerosis but, you also helped to raise over 115 million dollars for research into ALS otherwise known as Lou Gehrig’s disease. Very recently, researchers have been able to discover a gene that accounts for 3 percent of ALS cases known as NEK1. About 1 million dollars from the Ice Bucket Challenge was invested into a project known as Project MinE consisting of 11 countries and about 80 researchers. These researchers in turn were able to discover the NEK1 gene’s connection to the development of ALS.

            The NEK1 gene was discovered through the whole-exome analysis of over 1,000 individuals afflicted with familial ALS. The NEK1 gene discovered by researchers is very important to the nervous system. NEK1 is important in the maintenance of the cytoskeleton that gives neurons its shape and its ability to promote transportation within the neuron cells. NEK1 also has a big role in regulation of the mitochondria’s membrane. Other functions that NEK1 is associated with include cilia formation, DNA damage response, and microtubule stability. Once there is a problem in these functions due to the NEK1 gene being disabled or damaged, there is an increased chance for the development of ALS. Thankfully, now that NEK1 has been determined to be a gene of interest in regards to treating ALS, drug therapies can now be researched in targeting the NEK1 gene.

            To me, I'm glad to see that something that was a viral sensation throughout the world was able to do some good in discovering genes linked to ALS. I definitely believe that more good things are to come with this research not only in discovering more genes but also through social media in ways to help fund other researcher for other diseases. Although 30 genes have been discovered to have association with the cause of ALS, finding more and more genes related to it can help broaden treatment plans for those afflicted with ALS.

(http://www.nytimes.com/2016/07/28/health/the-ice-bucket-challenge-helped-scientists-discover-a-new-gene-tied-to-als.html?rref=collection%2Fsectioncollection%2Fhealth&action=click&contentCollection=health&region=stream&module=stream_unit&version=search&contentPlacement=10&pgtype=sectionfront)

A Certain Gene Increases the Progression of ALS

        Amoytrophic lateral sclerosis is a disease that involves the degeneration of the lower and upper motor neurons of the brainstem, resulting in those with the disease to loss of muscle control and ultimately death. One third of ALS patients are believed to have a gene that causes a faster progression of the disease. When mice were given this genetic variant, the disease progressed faster and the mice died sooner than the mice that did not have the genetic variant.
       
        About 10 years ago, researchers at Penn State found a link between the amount of iron accumulation in the brain in patients with nuerodegenerative disorders (Parkinson's and Alzheimer's disease). These researchers also found that about of third of their ALS patients had an accumulation of iron and had a genetic variant, HFE, that is associated with iron overdose diseases. In order to test the relationship between iron accumulation and the HFE variant, researchers crossbred mice with the HFE gene and standard mice.

This picture shows the difference between normal nerves and how the nerve fibers start to deteriorate and muscles weaken in those who have ALS.

        When studying the mice, James Connor, vice chair of neurosurgery research and director for the Center for Aging and Neurodegenerative Diseases, and his team found that the crossbred mice performed worse on test for hind limb and forelimb strength and had a 4% shorter life span. Their observations led them to conclude that when a mouse with the HFE variant was infected with ALS, the disease progressed much more rapidly than in the mice that did not have the variant. The grad student that was running the study, Wint Nandar, also realized that the females' disease progression was much faster in females with the variant than in males; however, normally, males with the disease would die faster than females.
 
        The researchers also found that the infected mice showed a greater degree of oxidative stress and microglial activation. Microglial cells are normally responsible for repairing the body, but when they are over-activated, they can cause inflammation, a factor that does not help with the progression of the disease. The mice with the genetic variant were also seen to have a disruption of the nuerofilaments, fibers that transport nutrients through the nerve cells, another reason why the disease can progress faster when HFE is present.

          I think that this a very important study that can be very valuable to those that are trying to find a cure for ALS, or some type of treatment. Knowing the genetic background an individuals can help researchers determine why some of their products work for some patients and not others. ALS is a very detrimental disease and anything that is going to hep researchers get a better understanding of the disease would be extremely beneficial.

Original Article: Genotype found in 30 percent of ALS patients speeds up disease progression

Identification of a Gene Associated with Familial ALS

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gherig's disease, is a fatal, "progressive, neurodegenerative disorder affecting the motor neurons in the central nervous system." As the motor neurons die, the brain loses its ability to communicate signals to the body's muscles, ultimately resulting in loss of voluntary muscle movement, paralysis, and eventual respiratory failure. According to the ALS association, the disorder affects 6-8 out of 100,000 people, and 10% of the cases are inherited. There is no cure for the disorder, and the cause of most cases is unknown.

A team of international scientists at the University of Massachusetts Medical School used exome sequencing in order to determine possible genes associated with familial ALS. This technique entails sequencing only the protein-coding genes in a genome. The team performed an exome-wide screen on 363 people with famililar ALS. Each subject also had a relative with the disorder. The team analyzed every coding gene in the genome of the subjects, specifically looking for patterns of rare, damaging mutations that are found more frequently in subjects with ALS.

Through their analysis, the team recognized an elevated frequency of  mutation in the TUBA4A gene in subjects with ALS. The team performed further analyses and was able to determine that the TUBA4A gene is associated with familial ALS. TUBA4A encodes for the protein Tubulin Alpha 4A.
Although the highest levels of the protein occur in the brain, the protein can be found in all human tissue. TUBA4A protein plays a vital role in the nerve cell. The protein "helps build the microtubule network, one of the most important structural components of the nerve cell" by moving the vital building blocks. The team found that mutated TUBA4A protein "is toxic to the neuron by weakening the entire microtubule network.

Landers, PhD, states that "identifying even rare mutations that could cause ALS" is of great importance as these mutations may lead to other common pathways that are changed before motor neuron death in ALS. The study also supports the idea that the cytoskeleton architecture and dynamics are crucial in the progression of ALS.

I was immediately drawn to this article after being bombarded by "Ice Bucket Challenges" all summer. Overall, I think it is really exciting that the TUBA4A was identified to be associated with familial ALS. Any advancements in this disorder are of great value to the scientific community as there is little knowledge regarding the disorder. Hopefully, with all of the donations and increased awareness of ALS, more studies like the one outlined in this article can be performed to gain more knowledge of the genetic roots of the disease.

Article: http://www.medicalnewstoday.com/releases/284333.php
Related Article:
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