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Jul 12
2019

Research Bit: New ALS gene that may be amenable to a rudimentary treatment: A precision medicine approach to neurodegeneration

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

Meeting Date: 12 July 2019

Presenter: Ruth Chia, PhD

Talk Title: New ALS gene that may be amenable to a rudimentary treatment: A precision medicine approach to neurodegeneration 

What was the question being asked?

Dr. Chia and colleagues were presented with a patient who had a rare, juvenile-onset case of ALS, the cause of which was unknown. By using genetic screening of the patient and members of the patient’s family, as well as screening a large cohort of healthy individuals, the researchers identified a patient-specific mutation in the gene serine palmitoyltransferase (SPTLC1). Dr. Chia then examined how this mutation may lead to cellular toxicity. 

Why is this important for ALS research?

Using a large cohort of more than 5600 ALS cases, Dr. Chia and colleagues were able to identify 17 novel mutations in this gene in 19 cases, making SPTLC1a new, though rare, cause of some ALS cases. Interestingly, different mutations in SPTLC1have been associated with a different disorder, hereditary sensory neuropathy type 1, and data from previous clinical trials in this disorder may be useful for ALS patients with this mutation. This research also implicated a new cellular process in ALS pathogenesis, which may have implications even for patients without mutations in SPTLC1

What was the take-home message?

SPTLC1 encodes an enzyme that is critical in producing certain lipids which make up cellular membranes. Mutations in SPTLC1 lead to abnormal activity of this crucial enzyme and the accumulation of toxic lipid metabolites within cells, presumably leading to cell death and in this case, a juvenile ALS phenotype. Importantly, these toxic byproducts can be used as a biomarker, which allows clinicians and researchers to track disease progression, and effects of a particular treatment. 

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

These results may lead to additional screening of ALS patients for mutations in SPTLC1, in addition to previously-established disease-associated genes. Additionally, previous clinical trials in hereditary sensory neuropathy type 1 (the other disease with mutations in SPTLC1)have also tested an inexpensive compound that can be used to ameliorate the disease phenotype, and early data suggests this compound may be useful in treating cells that harbor the ALS-associated mutations in SPTLC1, leading to a possible route for therapyfor patients with these specific mutations. Future work is needed to establish exactly how these mutations lead to motor neuron degeneration, and whether other cells are affected by the mutation as well.

 

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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