New ALS gene points to common role of cytoskeleton in disease

March 21, 2018, University of Massachusetts Medical School
KIF5A transports materials along the axon. It does this by serving as the anchor between the axon and the cargo. Credit: UMass Medical School

An international team of researchers led by John Landers, PhD, at UMass Medical School, and Bryan Traynor, MD, PhD, at the National Institute on Aging at the National Institutes of Health (NIH), has identified KIF5A as a new gene associated with the development of amyotrophic lateral sclerosis (ALS). The discovery, published in the journal Neuron, advances the understanding of what causes ALS and further implicates the role of cytoskeletal defects in the axon as a common factor in the disease. It points to the cytoskeleton as a potential target for new drug development.

"Identifying common mechanisms leading to ALS is essential in developing therapeutics for the disease," said Dr. Landers, professor of neurology. "Axonal transport deficits and cytoskeletal alterations are a pathological and genetic hallmark in ALS patients. Treatments that potentially stabilize or repair the cytoskeleton give us a target for developing drugs with the capability of treating both familial and sporadic ALS."

ALS is a that affects neurons in the brain and the spinal cord. People with ALS slowly lose the ability to initiate and control muscle movement, which often leads to total paralysis and death within two to five years of diagnosis. While 10 percent of ALS is familial in origin because of a genetic defect, the other 90 percent of ALS cases are considered sporadic, or without a family history. However, it is likely that genetics contribute, directly or indirectly, to a much larger percentage of ALS cases.

Patients with the KIF5A mutation exhibit a much longer survival period than other mutations. On average, people with the KIF5A mutation live approximately 10 years with ALS post-diagnosis.

The axon, a long, slender nerve fiber that projects from neurons, carries electrical impulses and other information in the form of proteins to nearby muscle cells. Defects in the structure that makes up the axon, called the cytoskeleton, can impair the neuron's ability to communicate with these cells. Similar defects in this function and cytoskeleton have been implicated by several genes that cause ALS.

KIF5A functions within neurons to transport material up and down the axon, a process known as axonal transport. KIF5A accomplishes this by acting like a chairlift transporting people and moving along cables in the axon's cytoskeleton. The KIF5A protein sits between the cables that run up and down the length of the axon and anchor, or carry, the materials being transported. Without KIF5A, materials that would otherwise be transported become marooned.

"Mutations in KIF5A join a growing list of known cytoskeletal-related gene mutations and strengthens the evidence of a role for cytoskeletal defects in the pathogenesis of ALS," explained Landers.

KIF5A also mediates the transport of RNA and RNA binding proteins. In so doing, it provides a link to a second pathway considered to be involved in ALS pathogenesis, RNA processing.

KIF5A mutations have been identified in patients with a rare form of hereditary spastic paraplegia (HSP), a slowly progressive neurodegenerative disease; the mutation that causes HSP is located near the start of the KIF5A protein. This region of the protein binds to the cytoskeleton, similar to the cable grip of a chairlift car. In contrast, ALS mutations cause the KIF5A protein to be truncated near its end, so that it doesn't make the full protein.

The KIF5A gene was discovered through a genome-wide search for ALS risk, comparing genomes from more than 20,800 ALS cases with 59,800 controls. Independently, a "rare variant burden analysis" was conducted on 1,138 familial ALS cases and 19,494 controls. Both approaches identified KIF5A as a novel gene associated with ALS.

The next step for Landers and colleagues is to better understand not only how truncations of the KIF5A protein lead to ALS, but also why do changes in a single amino acid near the beginning of the KIF5A protein cause HSP. This will include the development of novel mouse models with either ALS or HSP mutations. Additionally, induced pluripotent stem cells from ALS and HSP patients that have the KIF5A gene will be used to further explore the difference and commonalities resulting from these two . The goal, ultimately, is to facilitate the design of therapeutic approaches for these diseases.

"Funding from the ALS Association was instrumental for this project," said Landers. "This study represented the largest collaborative genetics effort in ALS."

The ALS Association provided support for the Project MinE ALS Sequencing Consortium, the NYGC ALS Consortium, the Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, and the Genomic Translation for ALS Care (GTAC) Consortium.

"Without the accomplishments and participation of each one of these groups, we would not have been successful in identifying this ALS gene," said Landers.

Explore further: New ALS associated gene identified using innovative strategy

Related Stories

New ALS associated gene identified using innovative strategy

October 22, 2014
Using an innovative exome sequencing strategy, a team of international scientists led by John Landers, PhD, at the University of Massachusetts Medical School has shown that TUBA4A, the gene encoding the Tubulin Alpha 4A protein, ...

New gene mutations linked to amyotrophic lateral sclerosis and nerve cell growth dysfunction

July 15, 2012
Researchers have linked newly discovered gene mutations to some cases of the progressive fatal neurological disease amyotrophic lateral sclerosis – ALS, also known as Lou Gehrig's disease. Shedding light on how ALS destroys ...

New gene variants present in three percent of all ALS patients

July 25, 2016
Variations in a gene with multiple functions in neurons are present in approximately 3 percent of all cases of ALS in North American and European populations, both sporadic and familial, making it one of the most common genetic ...

Supply bottleneck impairs nerve function

March 9, 2018
Impaired transport processes in neurons contribute to diseases such as amyotrophic lateral sclerosis (AML). Würzburg scientists have now identified key actors in these processes.

Resolving traffic jams in human ALS motor neurons

October 17, 2017
A team of researchers at VIB and KU Leuven used stem cell technology to generate motor neurons from ALS patients carrying mutations in FUS. They found disturbed axonal transport in these motor neurons, but also identified ...

Neurological disease in mice and humans linked to an unlikely gene

February 1, 2018
Screening for mutations influencing the migration of nerve cells in mice, scientists found a gene that plays a role in the transport of proteins within nerve cells. If less of the protein is present in the developing mouse, ...

Recommended for you

Silence is golden when it comes to how our brains work

June 18, 2018
It's the comparative silence between the firing spikes of neurons that tells what they are really up to, scientists report.

Observing brain plasticity during cello training

June 15, 2018
Music acquisition provides an excellent model of neural plasticity, and has become a hot research subject in neurology. Music performance provides an unmatched array of neural complexities revealing how neural networks are ...

New discovery about the brain's water system may prove beneficial in stroke

June 15, 2018
Water is transported from the blood into the brain via an ion transporter, according to a new study on mice conducted at the University of Copenhagen. If the mechanism can be targeted with medicine, it may prove relevant ...

Study shows how intensive instruction changes brain circuitry in struggling readers

June 14, 2018
The early years are when the brain develops the most, forming neural connections that pave the way for how a child—and the eventual adult—will express feelings, embark on a task, and learn new skills and concepts.

When emotional memories intrude, focusing on context could help, study finds

June 14, 2018
When negative memories intrude, focusing on the contextual details of the incident rather than the emotional fallout could help minimize cognitive disruption and redirect the brain's resources to the task at hand, suggests ...

The neurons that rewrite traumatic memories

June 14, 2018
Memories of traumatic experiences can lead to mental health issues such as post-traumatic stress disorder (PTSD), which can destroy a person's life. It is currently estimated that almost a third of all people will suffer ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.