There are many unanswered questions about ALS:
- Why does it start at a specific point, for instance, the thenar muscle, leading to the split-hand phenotype?
- Why does it spread to other muscle areas?
- Why do only some muscle types get affected and not others? For example, only skeletal muscles are impacted.
- Why are only muscles and motor neurons affected when TDP-43 pathology appears in many other tissues?
- Are we certain that the century-old explanation —where motor neurons die first, followed by muscle death— is correct? Some scientists believe it might be the other way around (backward dying). Also, why should only motor neurons die? Muscle cells and neurons both originate from the same progenitor cells, share many characteristics, are extremely long, and consume much more energy than other cells. So, probably, they should become dysfunctional simultaneously.
A young scientist might risk her entire academic future if she attempts to answer these questions. The research and subsequent publication only take small, cautious steps without challenging the long-standing paradigms.
In a study published in Nature Communications, Kazuhide Asakawa and colleagues utilized single-cell imaging in transparent zebrafish to demonstrate that large spinal motor neurons are subject to a constant, intrinsic burden of protein and organelle degradation.
While not revolutionary, this study confirms or clarifies previous findings:
- Large spinal motor neurons have inherently high autophagy and proteasome activity, possibly as an adaptation to higher protein-folding stress.
- Loss of TDP-43 intensifies these degradation processes, reflecting cellular stress responses.
- Despite this, large SMNs are still most vulnerable in ALS, suggesting their intrinsic protein stress exceeds their degradation capacity.
- Enhancing autophagy may be neuroprotective, indicating that supporting degradation pathways could help preserve motor neuron function.
The study relies on zebrafish, a vertebrate model sharing many conserved neuronal and autophagic mechanisms with humans. However, there are species-specific differences. Humans and zebrafish are both in the phylum Chordata —they have spinal cords— but they are quite different otherwise.
Nevertheless, components of autophagy and UPS pathways are likely similar across both species. These intracellular systems are part of cellular quality control, maintaining cell health. Since these mechanisms consume energy, they are less efficient in already starving cells.
TDP-43 biology is nearly identical in zebrafish and humans. Moreover, motor neuron subtype heterogeneity (large vs. small motor neurons) and vulnerability differences are conserved. Human large motor neurons, like those in the spinal cord’s ventral horn, are more vulnerable in ALS, while oculomotor neurons remain relatively unaffected, mirroring zebrafish observations.
The core relationship (Large motor neurons → higher protein stress → increased autophagy and UPS activity → vulnerability when overwhelmed) likely applies in humans, too.
Potential differences between zebrafish and humans include development and aging. Zebrafish neurons develop rapidly, so chronic aging-related effects —like decades of protein damage accumulation— are not modeled. Human neurons are larger and possess more complex synaptic networks, so issues with autophagic capacity might have more complex outcomes.
In terms of clinical implications, these findings may translate into:
A. Diagnostic or prognostic insights:
- Autophagic or proteasomal markers could indicate early neuronal stress or degeneration in ALS.
- Imaging or CSF biomarkers of autophagy overactivation might someday identify vulnerable motor neurons before death.
B. Therapeutic implications:
- Boosting degradation systems could be protective. Since enhancing autophagy and UPS activity seems beneficial, mild pharmacological stimulation might help. But treating most cells in the body is difficult, and these systems consume a lot of energy, which diseased cells lack.
- Targeting upstream protein misfolding—because large neurons accumulate misfolded proteins—might be beneficial through agents that improve protein folding, like ER chaperones or chemical chaperones (e.g., 4-PBA or TUDCA). However, similar attempts have shown limited results.
- Restoring TDP-43 function may help, as its loss causes splicing errors and degradation stress. Gene therapy or RNA-based fixes could indirectly normalize autophagy. Multiple approaches have been attempted, but complex, unresolved issues may remain.
In conclusion, this study is interesting but not groundbreaking. We need therapies that rejuvenate unhealthy cells; we won’t cure such a devastating disease with small steps alone.