ALS, also known as Lou Gehrig’s disease, is among the most challenging neurological disorders: relentlessly progressive, universally fatal, and without a cure even after more than a century and a half of research. Despite many advances, a key unanswered question remains—why do motor neurons, the cells that control body movement, degenerate while others are spared?
In their new study, Kazuhide Asakawa and colleagues used single-cell–resolution imaging in transparent zebrafish to show that large spinal motor neurons — which generate strong body movements and are most vulnerable in ALS — operate under a constant, intrinsic burden of protein and organelle degradation. These neurons maintain high baseline levels of autophagy, proteasome activity, and the unfolded protein response, suggesting a continuous struggle to maintain protein quality control.
Importantly, the team found that this burden is further amplified by the loss of TDP-43, a protein whose dysfunction is linked to most ALS cases. Initially, the acceleration of cellular degradation appears protective, supporting axon outgrowth. But over time, this heightened stress response may become overwhelmed, leading to the selective degeneration that characterizes ALS.
“Our findings suggest that the substantial size and metabolic demand of large motor neurons impose a constant degradation burden,” said Dr. Kazuhide Asakawa, lead author and principal investigator at the National Institute of Genetics. “This intrinsic pressure helps explain why these neurons are the first to degenerate in ALS, and points to reducing degradation burden as a potential therapeutic strategy.”
The study not only provides direct evidence of cell size–linked proteostatic stress in vulnerable neurons, but also offers new insight into an old puzzle in medicine: why ALS relentlessly targets motor neurons and remains so difficult to treat.
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About National Institute of Genetics (NIG)
National Institute of Genetics (NIG) was established to carry out broad and comprehensive research in genetics. NIG contributes to the development of academic research as one of the inter-university research institutes constituting the Research Organization of Information and Systems (ROIS).
About the Research Organization of Information and Systems (ROIS)
ROIS is a parent organization of four national institutes (National Institute of Polar Research, National Institute of Informatics, the Institute of Statistical Mathematics and National Institute of Genetics) and the Joint Support-Center for Data Science Research. It is ROIS's mission to promote integrated, cutting-edge research that goes beyond the barriers of these institutions, in addition to facilitating their research activities, as members of inter-university research institutes.
Nature Communications