Amyotrophic lateral sclerosis (ALS) is a fatal disease in which motor neurons that control voluntary movement gradually degenerate, leading to paralysis. Although many studies have been conducted, the reason why motor neurons are selectively affected has remained unclear.
Using transparent zebrafish that allow live imaging of nerve cells, we found that motor neurons constantly endure a burden to keep proteins properly folded (Figure 1). Larger neurons were particularly vulnerable, and this burden was further increased by genetic manipulations mimicking ALS.
Because motor neurons connect distant organs—brain, spinal cord, and muscles—with single cells, they must grow large and synthesize vast amounts of proteins, which increases their burden. This “inevitable degradation burden” may underlie their selective vulnerability in ALS. Even in tiny zebrafish larvae, such burden was detected, suggesting that in humans, whose motor neurons can reach as long as one meter in length, the challenge is far greater.
Understanding how this degradation burden arises may open the way to new therapeutic strategies to slow ALS progression and protect motor neurons from degeneration.
Figure: A) Large motor neurons show high protein degradation activity (autophagic flux). GFP-LC3 is degraded through autophagy. Arrows indicate large motor neurons with active GFP-LC3 degradation. B) Inhibition of autophagy impairs axonal development of motor neurons (right). Scale bars, 20 µm.
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