A New Therapeutic Angle for ALS

The Context: Amyotrophic lateral sclerosis (ALS) affects motor neurons, the cells that send signals to our muscles, gradually paralyzing patients. Scientists know that a mutation in a gene called C9orf72 contributes to ALS, but the exact mechanisms behind its impact are not well understood.

The Study: C9orf72 mutations alter a pathway that deals with mutant RNA expression, including a protein called eF1, which when increased suppress can rescue effects of the disease on neurons, finds a new study in Neuron by NYSCF – Robertson Investigator Dr. Evangelos Kiskinis.

The Importance: This study highlights the therapeutic potential of a new pathway in ALS.


Amyotrophic lateral sclerosis (ALS) is a devastating disease affecting the central nervous system, leading to muscle atrophy, paralysis, and eventually, death — all typically within 2-5 years of diagnosis. There is a desperate need for treatments that target ALS at its root, but to date, no such therapies exist.

A new study in Neuron by NYSCF – Robertson Stem Cell Investigator and NYSCF – Druckenmiller Fellow Alumnus Evangelos Kiskinis, PhD, of Northwestern Medicine uncovers how the largest genetic contributor to ALS could be leading to cellular dysfunction in the disease, pointing scientists toward new treatment options.

Researchers have known that a mutation in a gene called C9orf72 contributes to ALS by affecting motor neurons, the cells that send signals to our muscles. Specifically, having this mutation in your DNA leads to the formation of aberrant RNA (the molecules that help our cells make proteins) which causes dysfunction in motor neurons, but how this happens it isn’t exactly clear.

To investigate, Dr. Kiskinis’ team turned stem cells from ALS patients carrying a C9orf72 mutation into motor neurons and found that in response to the presence of atypical RNA, a protein called eF1, which normally lives in the cytosol, accumulates in the nuclei of the motor neurons. This sparks a pathway called ‘nonsense-mediated decay,’ which is responsible for breaking down aberrant RNA

“This study is exciting because, based on an unbiased approach, our findings pointed to a specific RNA degradation pathway, which may be a key underlying component of disease,” Elizabeth Daley, a graduate student in Dr. Kiskinis’ lab and co-lead author of the study, tells Northwestern Medicine News Center.

Finding a way to stimulate this pathway could be key to development of new treatments, and Dr. Kiskinis plans to address this possibility in future studies.

Journal Article:

Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense-Mediated Decay as Modifiers of ALS/FTD C9orf72 Toxicity
Juan A. Ortega, Elizabeth L. Daley, Sukhleen Kour, Marisa Samani, Liana Tellez, Haley S. Smith, Elizabeth A. Hall, Y. Taylan Esengul, Yung-Hsu Tsai, Tania F. Gendron, Christopher J. Donnelly, Teepu Siddique, Jeffrey N. Savas, Udai B. Pandey, Evangelos Kiskinis. Neuron. February 2020. DOI: https://doi.org/10.1016/j.neuron.2020.01.020

Diseases & Conditions:

ALS (Lou Gehrig's Disease)

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