KIF5A Gene Discovery Feature Interview with Dr. John Landers

We sat down with Dr. John Landers, professor of Neurology at the University of Massachusetts Medical School, to discuss the recent discovery of the newest ALS gene, KIF5A, made possible by The ALS Association funding through ALS Ice Bucket Challenge donations. Dr. Landers is the co-leader of the U.S. arm of Project MinE, which is the largest ALS whole genome sequencing effort of its kind. The discovery findings were published in the journal Neuron.

This massive collaborative effort between researchers from Project MinE, Genomic Translation for ALS Care, Answer ALS, the New York Genome Center (NYGC) ALS Consortium, the CReATe Consortium, the Target ALS Postmortem Tissue Core, the National Institutes of Health (NIH), and others supported or funded in some way by The ALS Association contributed to this gene discovery.

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Dr. John Landers

How did The ALS Association donations support your project?

Funding from The ALS Association was instrumental for this project. This study represented the largest collaborative genetics effort in ALS. Funding from The ALS Association provided support for several distinct efforts that were able to contribute to the overall goal of identifying and confirming a novel gene contributing to ALS.

This project includes, but is not limited to, 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.

 How did all the collaborative partnerships involved in this gene discovery work come together to work so effectively?

The common goal of the ALS scientific community is to advance our understanding of the disease and ultimately develop therapeutic treatments. Each member of the consortium contributing to this effort did so with the intent that their participation advances our understanding of ALS and that each new finding brings us one step closer to our overall goal.

 What is the most important finding of your paper and why?

Identifying common pathways leading to ALS is essential in developing therapeutics for the disease. The study of genes associated with human diseases is commonly performed to help reveal those pathways. Our paper describes the identification of KIF5A as a novel gene associated with the development of ALS.

KIF5A functions within neurons to transport material within the axon, otherwise known as axonal transport. Axons transmit information to different neurons or muscles via axonal transport. Neurons normally move materials along their axons to keep nerve cell messages flowing and to maintain the health of the whole neuron.

KIF5A contributes to axonal transport by acting similar to a chairlift transporting people. It moves material along cables in the axon, called the cytoskeleton. The cell cytoskeleton is a complex network of interlinking filaments that help give a cell its shape and organize its parts.

Mutations in KIF5A also join a growing list of cytoskeletal related genes and strengthens the role of cytoskeletal defects in ALS disease. Similarly, axonal transport deficits and cytoskeletal alterations are a hallmark pathological feature in people with ALS.

Furthermore, KIF5A mediates the transport of RNA (the building blocks of protein) and RNA binding proteins. As such, it provides a link to a second pathway considered to be involved in ALS disease, RNA processing. RNA is the instruction book for making protein and RNA must be modified or processed in several ways before it is made into protein.

KIF5A mutations have previously been identified in patients with SPG10, a rare form of hereditary spastic paraplegia (HSP), a slowly progressive neurodegenerative disease. Interestingly, SPG10/HSP mutations are located near the beginning of the KIF5A protein and change the composition of a single amino acid. This region of the protein functions to bind to the cytoskeleton, similar to the cable grip of a chairlift car.

In contrast, ALS mutations cause the KIF5A protein to be shortened near its other end, meaning that the full KIF5A protein is not made. This region of the KIF5A protein functions to bind to the cargo, similar to the seating region of the chairlift.

These observations demonstrate that the functional domain mutated in KIF5A dictates the observed clinical characteristics in patients, resulting in distinct, yet overlapping neurodegenerative diseases.

Lastly, familial (inherited) ALS patients with KIF5A mutations display a greatly extended survival, nearly 10 years on average, compared to the two- to three-year survival of typical ALS patients.

What is the impact of your paper on the ALS field and ALS community?

The identification of KIF5A as an ALS associated gene has several areas of impact on the ALS field and community. First off, the identification of any new gene furthers our understanding of the primary pathways that contribute to ALS. As mentioned above, discovery of mutations in KIF5A joins a growing list of cytoskeletal related genes and strengthens the role of cytoskeletal defects in ALS disease. As such, targeting the cytoskeleton may be an approach for therapeutic interventions.

Additionally, the identification of new genes provides the opportunity to develop new animal models for ALS, which can promote additional research into understanding the disease, as well as a method of testing novel therapeutic approaches.

Furthermore, since mutations in different domains of KIF5A dictates the clinical phenotype of HSP vs. ALS, we can exploit this observation to further understand how these distinct, yet overlapping neurodegenerative diseases develop.

Although KIF5A mutations are rare in ALS, clinical screening may help to confirm the diagnosis. Furthermore, our results suggest that ALS patients with KIF5A mutations demonstrate a longer survival, which is of clinical significance. The median survival of ALS patients overall is approximately two-three years. Interestingly, patients with mutations in KIF5A exhibit a median survival of nearly 10 years.

What research is currently being done, and what are the next steps to move the understanding of the KIF5A gene forward?

My laboratory has initiated several steps 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/SPG10, a related yet distinct neurodegenerative disease. These steps include the development of mouse models which harbor either ALS or HSP mutations, in collaboration with Dr. Cathleen Lutz at Jackson Laboratory.

Additionally, we are developing induced Pluripotent Stem Cells (iPSC) from ALS and HSP patients that harbor mutations in the KIF5A gene. iPSCs have an embryonic-like pluripotent state that allows them to be differentiated into essentially any cell type including motor neurons, the main cell type affected in ALS patients.

In both cases, understanding the differences and commonalities resulting from these mutations will further our comprehension of the steps leading to ALS and HSP and ultimately facilitate the design of therapeutic approaches for these diseases. Additionally, we are developing drug screening assays based on defects that we observe in mutant KIF5A expressing cells.

 

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