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Jul 12
2019

Research Bit: Genetic analysis identifies pathways and cell types involved in amyotrophic lateral sclerosis

Research Bits
The Packard Center welcomed Sara Saez from the National Institutes of Health to a recent Investigator's Meeting.

Meeting Date: 12 July 2019

Presenter: Sara Saez, PhD

Talk Title: Genetic analysis identifies pathways and cell types involved in amyotrophic lateral sclerosis 

What was the question being asked?

Dr. Saez uses large datasets of healthy subjects to identify how small changes in our genome can combine with one another to influence our lifetime risk of getting ALS. By surveying lots of genetic changes with unknown disease-relevance at once, as opposed to studying a few rare disease-associated mutations at a time, Dr. Saez hopes to have a broader picture of how our genes can influence our risk of ALS, and then apply these findings in disease models to study their effect on cell biology and disease progression. 

Why is this important for ALS research?

The vast majority of ALS cases occur sporadically, meaning patients have no known genetic cause for their ALS. This is frustrating for both patients and researchers alike, because it is difficult to study a disease and find effective treatments when the cause is unknown. Large genome-wide association studies (GWAS) have previously been used to identify genes which might be linked to ALS, but these studies often only pick out rare genetic variants, and are not capable of finding many smaller mutations. On their own, these small changes might not be associated with ALS, but when they occur in the presence of other small changes, this combination may have a strong effect on ALS risk. Her bioinformatic method also allows her to study which cellular pathways, and which specific cell types, may play greater roles in ALS as opposed to others. 

What was the take-home message?

Combined changes in genes involved in the cell’s process of trafficking proteins to the plasma membrane, which is essential for cell function and cell-cell signaling, were associated with a higher combined risk of ALS than other signaling pathways. Additionally, changes in genes enriched in certain cell populations, such as oligodendrocytes and dopaminergic neurons, were also predicted to lead to greater risk of ALS. The functional outcome of these changes is not clear yet, and needs to be validated in biological models.

How do you think the results of this study might impact future approaches to the treatment of ALS? 

These studies may lead to changes in the way researchers and clinicians think about finding genes involved in ALS pathogenesis. While many diseases are caused by or are associated with a specific genetic mutation, in other cases like sporadic ALS, researchers may start looking for how a person’s individual small mutations may combine and influence their risk of ALS. This can have implications for how researchers search for biomarkers of disease, a measurement which is crucial for designing and testing clinical therapies.  

Jenna C. Glatzer
PhD Candidate, Cellular and Molecular Medicine Graduate Program
Laboratories of Dwight Bergles and Jeff Rothstein 
Johns Hopkins University School of Medicine 

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