ALS patients sometimes say that there is a "special skin" associated with ALS. It would appear that this is true. A new study shows that the TDP-43 pathology develops throughout the body, up to ten years before diagnosis.

Understanding the mechanisms of amyotrophic lateral sclerosis (ALS) remains a major challenge in neurodegenerative research. Although the diagnosis of ALS is based on motor symptoms, the underlying pathology develops silently for years. A growing body of evidence suggests that these early pathological events could be detectable outside the central nervous system (CNS), well before the onset of clinical symptoms.

A recent study has explored this possibility in depth. The scientists used new tools to explore the TDP-43 pathology. Conventional staining with anti-phospho-TDP-43 antibodies did not reveal any aggregates in the muscle samples. This study highlights the potential of RNA-based detection tools for the early diagnosis of pathologies.

Using sensitive molecular tools, the authors examined the early manifestation of TDP-43 pathology in the peripheral organs of individuals who later developed ALS across several databases. Their findings highlight the skin as a particularly promising source of pre-symptomatic biomarkers, with the pathology sometimes detectable more than 20 years before the onset of symptoms. The first part of the study examined tissue biopsies from eight different organ systems, taken from living individuals who later developed ALS. Importantly, the authors employed two novel, highly sensitive approaches. They initially detected abnormalities in the skin of 7 patients, and then in various non-brain sites in the bodies of 17 patients:

• Skin

• Muscle

• Colon

• Gallbladder

• Lymph nodes

The affected cell types share a common developmental origin with the central nervous system.

In these individuals, abnormalities appeared:

• Up to 11 years before the onset of symptoms in the skin

• Up to 14 years before the onset of symptoms in the lymph nodes

• 1 to 2 years before the onset of symptoms in the gastrointestinal tissues

In one person who had two biopsies performed in the same location several months apart, early pathology appeared between the two biopsies. This suggests a real-time transition from normal to abnormal tissue, potentially reflecting a phenomenon of "phenoconversion."

In the validation cohort, a wide range of anatomical sites were affected: head and neck, trunk, perineal region, and limbs. The pathology was diffuse regardless of the sampling site. Muscle tissue also exhibited previously undetectable abnormalities. Sweat glands showed the most consistent and intense signal, making them excellent candidates for the development of quantifiable biomarkers. Areas protected from the sun had a higher pathological burden than sun-exposed areas.

These results also suggest widespread peripheral immune and vascular involvement.

These results underscore the potential for developing minimally invasive early detection tests using skin biopsies. Although further studies are needed, particularly with larger and more diverse cohorts, the data presented suggest that cutaneous TDP-43 tests could become valuable tools for early diagnosis, risk assessment, and future clinical trials aimed at pre-symptomatic intervention.

Implications for ALS Research and Treatment

1. Reassessment of Pathogenesis

These results support the hypothesis that ALS may be a TDP-43 proteinopathy predominantly affecting the central nervous system, rather than a disease exclusively affecting motor neurons. Researchers must now determine whether pathology of peripheral tissues (such as sweat glands in the skin or nerves in the intestine) is simply a transient phenomenon or actively contributes to disease progression. It is possible that peripheral pathology fuels CNS pathology in a phenomenon of "retrograde degeneration," overloading motor neurons in the spinal cord and brain.

2. Expanding Therapeutic Targets

While ALS is a systemic disease, drug development should not focus solely on the brain and spinal cord. Therapies targeting the underlying cause of TDP-43 protein dysfunction in peripheral tissues are becoming increasingly important.

More readily accessible sites, such as skin or blood, could be easier to administer while offering protection to motor neurons.

3. Early diagnosis is now possible

As the study has shown, the diffuse nature of the pathology makes it an ideal candidate for early diagnosis. A skin biopsy becomes a relatively non-invasive and accessible tool for detecting the disease decades before the onset of clinical symptoms, thus providing a crucial window for preventive therapies.

In short, the diffuse nature of the pathology does not call into question the involvement of motor neurons, but rather places it in context. It strongly suggests that motor neuron degeneration is the serious clinical consequence of a more widespread systemic cell failure, caused by a dysfunction of the TDP-43 protein.

New Perspective on ALS: How Muscles Regulate TDP-43 at the Synapse

For many years, SOD1-related ALS was considered a special case within the disease spectrum: a subtype of ALS where the TDP-43 protein, which characterizes the pathology of most ALS cases, played a minor or even nonexistent role. This hypothesis is now being challenged. A recent study reveals that the TDP-43 protein is strongly implicated in SOD1-related ALS, but in a way that had escaped previous observations: the pathology appears to be located not in the cell bodies of motor neurons, but in the axons and at the neuromuscular junction (NMJ).

This shift in perspective alters our understanding of the early pathology of ALS and opens new therapeutic avenues focused on the synapse, or even on the muscle itself.

When pathologists examine the spinal motor neurons of patients with SOD1-related ALS, the nuclei generally appear normal: the TDP-43 protein is always present, and abnormal aggregates are rarely observed. This is why SOD1-related ALS has been considered "TDP-43 negative."

However, this study reveals that the situation is very different in the periphery. In patients with SOD1-related ALS and in SOD1 mouse models (G93A and G37R): Phosphorylated TDP-43 protein forms aggregates in peripheral motor axons. TDP-43 protein accumulates early at the neuromuscular junction, well before the onset of symptoms. Yet the cell bodies of the motor neurons remain normal, with intact nuclear TDP-43 protein.

This article represents a non-canonical form of TDP-43 pathology. The lesions are concentrated at the synapses at the ends of the very long axons, not at the soma. This distinction is important because ALS often begins with regressive degeneration, with deterioration of the neuromuscular junction (NMJ) preceding motor neuron death. Motor neurons rely heavily on local translation for the maintenance of mitochondria, vesicles, and cytoskeletal components. An excess of TDP-43 at the terminal inhibits these processes.

Local TDP-43 Synthesis: An Unsuspected Vulnerability

Motor axons are extremely long and depend on local protein synthesis to maintain their terminals. The study above shows that TDP-43 itself is one of these locally regulated proteins. Under normal conditions, this translation is maintained at a low level.

This local pool of TDP-43 appears harmless when tightly controlled. But when its regulation is disrupted, the axon becomes vulnerable to an excess of TDP-43 and its known ability to inhibit the translation of many other mRNAs.

The study shows that muscle actively inhibits presynaptic TDP-43 via exosomes. The muscle is not, as previously thought, a passive player in the biology of the neuromuscular junction (NMJ). Muscle releases extracellular vesicles (EVs) loaded with regulatory molecules that influence the motor axon. These muscle-derived EVs contain miR-126-5p, a microRNA that strongly represses the translation of TDP-43, AGO2, and other components of RNA silencing pathways.

Motor axons at the neuromuscular junction (NMJ) take up these vesicles, which helps control local TDP-43 synthesis. Muscle thus exerts a protective trans-synaptic influence on the neuron.

In ALS, this protective system malfunctions.

In SOD1-related ALS, the study reveals a sharp decrease in miR-126-5p levels. When miR-126-5p levels drop, the inhibition of local TDP-43 production is lifted. This leads to excessive TDP-43 synthesis at presynaptic axonal terminals, decreased local protein synthesis, and ultimately, failure and degeneration of the neuromuscular junction (NMJ). Motor neurons are structurally fragile. Their considerable length makes them particularly dependent on local protein synthesis. Localized blockage of this synthesis can lead to denervation, even if the soma is intact.

This mechanism establishes a direct link between early NMJ degeneration and TDP-43 toxicity, even when the latter has not yet left the nucleus.

Inhibition of miR-126-5p at the neuromuscular junction

TDP-43 toxicity is generally associated with its nuclear loss: TDP-43 leaves the nucleus, its normal RNA maturation functions are impaired, and DNA damage or splicing errors ensue. This study highlights another problem: a local excess of TDP-43 can be harmful even when nuclear TDP-43 is intact.

The authors tested their hypothesis by blocking the release of extracellular vesicles (EVs) are released from the muscle. These manipulations produced the same effects as those observed in ALS: increased axonal TDP-43, reduced local translation, and neuromuscular junction (NMJ) degeneration. Importantly, administration of siRNAs targeting TDP-43 prevented this degeneration, demonstrating that TDP-43 overabundance at the synapse is the determining factor.

Stimulating miR-126 can improve neuromuscular junction (NMJ) function

When researchers restored miR-126 levels in SOD1 mice, NMJ structure and function improved, and pathological markers decreased. Although these are preliminary therapeutic experiments, they pave the way for new intervention strategies that act at the synapse rather than the nucleus.

Therapeutic Implications

The study suggests several treatment avenues, each requiring rigorous and realistic evaluation, but above all, muscle rather than the motor neuron is emerging as a therapeutic target.

Traditionally, ALS treatments have targeted the neuron. However, muscle appears as a promising site of intervention because it naturally regulates presynaptic protein homeostasis via extracellular vesicles (EVs). Given that blocking EV secretion accelerates degeneration, maintaining healthy EV trafficking could have protective effects. If synaptic accumulation is an early and distinctive event, interventions aimed at eliminating or reducing these aggregates—including antisense strategies—could prove valuable, even in ALS types previously thought to be independent of the TDP-43 protein.

Convergence Among ALS Subtypes

More broadly, the discovery of TDP-43 pathology in SOD1-related ALS suggests downstream mechanisms common to several ALS variants. This could allow for the unification of therapeutic approaches rather than their fragmentation based on genotype.

This study renews our understanding of the TDP-43 protein in ALS, particularly in SOD1 models. Instead of a nuclear problem at the motor neuron level, the lesions result from a dysregulation of local translation at the synapse. The usual role of muscle in limiting TDP-43 production is altered, allowing the formation of toxic aggregates at the neuromuscular junction and weakening the connection between the nerve and muscle.

By highlighting an early mechanism acting outside the central nervous system, this work paves the way for both innovative and potentially more accessible therapeutic strategies: restoring the muscle-derived miR-126, supporting signaling via extracellular vesicles, and targeting synaptic TDP-43 before it destabilizes the entire motor unit.

If future studies confirm these results, the neuromuscular junction—or even the muscle itself—could represent one of the most promising targets for early intervention in ALS.

Nouvelle perspective sur la SLA : Comment les muscles réguleraient la protéine TDP-43 au niveau de la synapse.

Pendant de nombreuses années, la SLA liée à la SOD1 a été considérée comme un cas particulier au sein du spectre de la maladie : un sous-type de SLA où la protéine TDP-43, qui caractérise la pathologie de la plupart des cas de SLA, jouerait un rôle mineur, voire inexistant. Cette hypothèse est aujourd’hui remise en question. Une étude récente révèle que la protéine TDP-43 est fortement impliquée dans la SLA liée à la SOD1, mais d’une manière qui avait échappé aux observations précédentes : la pathologie se situerait non pas dans les corps cellulaires des motoneurones, mais dans les axones et à la jonction neuromusculaire (JNM).

Ce changement de perspective modifie notre compréhension de la pathologie précoce de la SLA et ouvre de nouvelles pistes thérapeutiques axées sur la synapse, voire sur le muscle lui-même. Lorsque les pathologistes examinent les motoneurones spinaux de patients atteints de SLA liée à SOD1, les noyaux apparaissent généralement normaux : la protéine TDP-43 est toujours présente et les agrégats anormaux sont rarement observés. C’est pourquoi la SLA liée à SOD1 a été considérée comme « TDP-43 négative ».

Cependant, cette étude révèle que la situation est très différente en périphérie. Chez les patients atteints de SLA liée à SOD1 et dans les modèles murins SOD1 (G93A et G37R) : La protéine TDP-43 phosphorylée forme des agrégats dans les axones moteurs périphériques. La protéine TDP-43 s’accumule précocement à la jonction neuromusculaire, bien avant l’apparition des symptômes. Les corps cellulaires des motoneurones restent normaux, avec une protéine TDP-43 nucléaire intacte.

Ce schéma représente une forme non canonique de pathologie TDP-43. Les lésions sont concentrées au niveau des synapses au bout du très long axone, et non du soma. Cette distinction est importante car la SLA débute souvent par une dégénérescence régressive, la détérioration de la jonction neuromusculaire (JNM) précédant la mort des motoneurones. Les motoneurones dépendent fortement de la traduction locale pour le maintien des mitochondries, des vésicules et des éléments du cytosquelette. Un excès de TDP-43 à la terminaison inhibe ces processus.

Synthèse locale de TDP-43 : une vulnérabilité insoupçonnée

Les axones moteurs sont extrêmement longs et dépendent de la synthèse protéique locale pour maintenir leurs terminaisons. L’étude ci-dessus montre que la TDP-43 elle-même est une de ces protéines régulées localement. Dans des conditions normales, cette traduction est maintenue à un faible niveau.

Ce pool local de TDP-43 semble inoffensif lorsqu’il est étroitement contrôlé. Mais lorsque sa régulation est perturbée, l’axone devient vulnérable à un excès de TDP-43 et à sa capacité connue à inhiber la traduction de nombreux autres ARNm.

L'étude montre que muscle inhibe activement la TDP-43 présynaptique via les exosomes. Il n'est pas comme on le croyait jusque là, un acteur passif dans la biologie de la JNM. Le muscle libère des vésicules extracellulaires (VE) chargées de molécules régulatrices qui influencent l'axone moteur. Ces VE d'origine musculaire contiennent  miR-126-5p, un microARN qui réprime fortement la traduction de TDP-43, AGO2 et d'autres composants des voies de silençage de l'ARN.

Les axones moteurs de la jonction neuromusculaire (JNM) absorbent ces vésicules, ce qui contribue à contrôler la synthèse locale de TDP-43. Le muscle exerce ainsi une influence trans-synaptique protectrice sur le neurone.

Dans la SLA, ce système protecteur est défaillant.

Dans la SLA liée à SOD1, l'étude révèle une forte diminution du taux de miR-126-5p, lorsque le taux de miR-126-5p chute, l'inhibition de la production locale de TDP-43 est levée. Il y a alors une synthèse excessive de TDP-43 au niveau des terminaisons axonales présynaptiques, une diminution de la synthèse protéique locale et à terme une défaillance et dégénérescence de la jonction neuromusculaire (JNM). Les motoneurones sont structurellement fragiles. La longueur considérable de ces cellules les rend particulièrement dépendantes de la synthèse protéique locale. Un blocage localisé de cette synthèse peut entraîner une dénervation, même si le soma est intact.

Ce mécanisme établit un lien direct entre la dégénérescence précoce de la JNM et la toxicité du TDP-43, même lorsque ce dernier n’a pas encore quitté le noyau.

Inhibition de miR-126-5p au niveau de la jonction neuromusculaire

La toxicité de TDP-43 est généralement associée à sa perte nucléaire : TDP-43 quitte le noyau, ses fonctions normales de maturation de l'ARN sont altérées, et des lésions de l'ADN ou des erreurs d'épissage s'ensuivent. Cette étude met en lumière un autre problème : un excès local de TDP-43 peut être nocif même lorsque le TDP-43 nucléaire est intact.

Les auteurs ont testé leur hypothèse en bloquant la libération de vésicules extracellulaires (VE) par le muscle. Ces manipulations ont produit les mêmes effets que ceux observés dans la SLA : augmentation du TDP-43 axonal, réduction de la traduction locale et dégénérescence de la JNM. Fait important, l’administration d’ARNsi ciblant le TDP-43 a empêché cette dégénérescence, démontrant que la surabondance de TDP-43 au niveau de la synapse en est le facteur déterminant.

Stimuler le miR-126 peut améliorer la fonction de la jonction neuromusculaire (JNM)

Lorsque les chercheurs ont rétabli les niveaux de miR-126 chez des souris SOD1, la structure et la fonction de la JNM se sont améliorées et les marqueurs pathologiques ont diminué. Bien qu'il s'agisse d'expériences thérapeutiques préliminaires, elles ouvrent la voie à de nouvelles stratégies d'intervention agissant au niveau de la synapse plutôt qu'au niveau du noyau.

Implications thérapeutiques

L'étude suggère plusieurs pistes de traitement, chacune nécessitant une évaluation rigoureuse et réaliste, mai surtout le muscle plutôt que le neurone moteur devient une cible thérapeutique.

Traditionnellement, les traitements de la SLA ciblent le neurone. Or, le muscle apparaît comme un site d'intervention prometteur, car il régule naturellement l'homéostasie des protéines présynaptiques via les vésicules extracellulaires (VE). Étant donné que le blocage de la sécrétion des VE accélère la dégénérescence, le maintien d'un trafic sain de VE pourrait avoir des effets protecteurs. Si l'accumulation synaptique est un événement précoce et distinctif, les interventions visant à éliminer ou à réduire ces agrégats – y compris les stratégies antisens – pourraient s'avérer précieuses, même dans les types de SLA que l'on pensait auparavant indépendants de la protéine TDP-43.

Convergence entre les sous-types de SLA

Plus largement la découverte de la pathologie TDP-43 dans la SLA liée à SOD1 suggère des mécanismes en aval communs à plusieurs variantes de la SLA. Ceci pourrait permettre d'unifier les approches thérapeutiques plutôt que de les fragmenter selon le génotype.

Cette étude renouvelle notre compréhension de la protéine TDP-43 dans la SLA, en particulier dans les modèles SOD1. Au lieu d'un problème nucléaire au niveau du motoneurone, les lésions résultent d'une dérégulation de la traduction locale au niveau de la synapse. Le rôle habituel du muscle dans la limitation de la production de TDP-43 est altéré, ce qui permet la formation d'agrégats toxiques à la jonction neuromusculaire et affaiblit la connexion entre le nerf et le muscle.

En mettant en lumière un mécanisme précoce, agissant en dehors du système nerveux central, ces travaux ouvrent la voie à des stratégies thérapeutiques à la fois novatrices et potentiellement plus accessibles : la restauration du miR-126 d'origine musculaire, le soutien de la signalisation par vésicules extracellulaires et le ciblage du TDP-43 synaptique avant qu'il ne déstabilise l'ensemble de l'unité motrice.

Si de futures études confirment ces résultats, la jonction neuromusculaire – voire le muscle lui-même – pourrait constituer l'une des cibles les plus prometteuses pour une intervention précoce dans la SLA.

Il y a environ 15 000 articles scientifiques par an au sujet de la SLA et chaque année environ une cinquantaine de ces articles clament avoir fait un progrès décisif dans la lutte contre cette maladie. On pourrait se réjouir de cet intérêt scientifique et des ressources immenses qui seraient apparemment impliquées dans cette recherche.

En fait il y a une découverte majeure dans le domaine de la SLA seulement toutes les quelques années.

D'où vient cette différence entre ces deux faits? La publication d'articles scientifiques est un moyen d'obtenir des fonds et de faire progresser une carrière. Si un auteur veut publier rapidement un article, mais en évitant d'être scruté par des milliers de lecteurs, il est tentant de publier dans un domaine obscur où le nombre de spécialistes est très réduit par rapport à un domaine comme la recherche sur le cancer.

De plus, nombre de scientifiques ne lisent pas les articles publiés par leurs pairs, ils se contentent de lire l'abstract et appliquent des filtres mentaux. Il est alors tentant pour un auteur malhonnête de publier un abstract qui exagère considérablement les résultats obtenus. Et c'est sans compter le dossier de presse de l'université qui en général est tellement dithyrambique qu'il en est comique, sauf pour les malades et leur famille.

Diverses études ont montré qu'un tiers des articles scientifiques dans le domaine biologique/médical ne sont pas reproductibles.

L'article dont nous parlons aujourd'hui est un rafraichissement considérable par rapport à ces pratiques nauséabondes. Les auteurs, Morgan Highlander et Sherif Elbasiouny, y examinent une étude récente d'Ahmed et al.,

qui affirme qu'une forme de stimulation électrique spinale (« DCS multivoies ») améliore considérablement la survie et la fonction motrice chez la souris SOD1-G93A, un modèle de SLA. Bien que les effets rapportés semblent impressionnants – notamment une amélioration de la survie de 74 % –, les auteurs affirment qu'un examen détaillé de la méthodologie révèle plusieurs problèmes critiques qui fragilisent considérablement ces conclusions.

Utilisation trompeuse des indicateurs de survie

Le chiffre principal de l'étude (survie prolongée de 74 %) est basé sur le délai entre l'apparition des symptômes et l'arrêt du traitement, et non sur la durée de vie totale. Cet indicateur n'est pas une mesure standard de la survie dans la recherche sur la SLA et dépend fortement de la méthode de détection de l'apparition des symptômes – une évaluation qui peut être subjective. Lorsque la durée de vie totale est examinée directement, l'amélioration réelle n'est que d'environ 5 %, et non de 74 %.

Cela est évident quand on regarde les figures de l'article d'Ahmed et al. Analyses statistiques contestables

Les auteurs de l'article d'Ahmed et al. appliquent des tests statistiques sans vérifier que les données respectent les hypothèses requises pour ces tests. Le groupe non stimulé ayant enregistré deux décès exceptionnellement précoces, le bénéfice de survie surestimé pourrait être largement dû à ces valeurs aberrantes.

Détection non validée et probablement tardive de l'apparition des symptômes

La date rapportée d'apparition des premiers symptômes semble bien plus tardive que celle généralement observée, ce qui suggère que les symptômes ont pu être détectés beaucoup trop tard.

Contradictions et incohérences dans les données supplémentaires

Une expérience supplémentaire, où la stimulation a débuté à un âge fixe, n'a montré aucun bénéfice en termes de survie.

Les résultats concernant la fonction motrice proviennent de seulement 8 des 48 animaux, sans explication des critères utilisés pour la sélection de ces 8 animaux. Aucun test statistique n'a été réalisé et le test de marche sur grille utilisé dans l'étude n'est ni standard ni validé pour les modèles de SLA. Les scores étant uniquement exprimés en fonction du « jour après l'apparition des symptômes », les résultats ne peuvent être comparés aux schémas d'évolution connus de la maladie.

Preuves histologiques insuffisantes L'analyse tissulaire, censée mettre en évidence une réduction des marqueurs de la maladie et la préservation des neurones, manque de précisions méthodologiques essentielles. Des éléments clés tels que la stratégie d'échantillonnage, les critères d'imagerie et les contrôles ne sont pas décrits. Certains résultats semblent clairement influencés par des valeurs aberrantes. Les contrôles de base (par exemple, la confirmation de l'identité des neurones ou la normalisation des signaux de fluorescence) sont absents. Globalement, les données histologiques n'apportent pas d'éléments probants en faveur des effets du traitement.

Conclusion

Morgan Highlander et Sherif Elbasiouny soutiennent que l’étude d’Ahmed et al. ne répond pas aux exigences de rigueur attendues dans la recherche préclinique sur la SLA. Le bénéfice en termes de survie est surestimé, les analyses statistiques sont erronées, la méthode de détection de l’apparition des symptômes n’est pas validée et les résultats fonctionnels et histologiques sont peu étayés.

Sachant que des résultats précliniques surestimés ont déjà contribué à l’échec d’essais cliniques sur la SLA, les auteurs, Morgan Highlander et Sherif Elbasiouny, insistent sur l’importance de méthodologies robustes et transparentes. Ils préconisent une révision substantielle de l’analyse et de la présentation des résultats de l’étude avant que sa valeur thérapeutique ne puisse être évaluée de manière fiable.

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.

A year ago, a new study drew attention because it was a "hopeful anomaly." It challenged the fatalistic narrative of ALS and provided a clear, new direction for this research field. The ALS therapeutic landscape has seen many failures. Most drugs only slow the disease slightly. For those living with ALS, this study was a concrete reason for hope.

The idea that the secrets to curing the disease might be found in rare individuals who mysteriously recover is a compelling story. It suggests that the biological processes of ALS aren't always one-way and that recovery, though rare, might be possible.

Now, some readers have published a response to this study.

It's behind a paywall, so I haven’t read it, but I can guess what it says. Additionally, a recent publication states: "variants in IGFBP7 were linked to rare "ALS reversals," but the existence of such cases remains controversial." https://pmc.ncbi.nlm.nih.gov/articles/PMC12419016/

In the study published last year, researchers told that they gathered 22 documented reversal cases and validated them across the Target ALS database. This was a pilot case-control study at Duke ALS Clinic in Durham, North Carolina.

The investigators collected demographics, disease details, pedigree info, and saliva samples from ALS reversals. Whole-genome DNA was extracted and sequenced from these saliva samples. The genomes of ALS reversals were then compared to previous whole-genome sequences from a biorepository of de-identified samples of more typical ALS patients. https://clinicaltrials.gov/study/NCT03464903

The researcher has confirmed 34 of these "reversal" cases so far by reviewing medical records. These patients differ in demographics and disease features compared to typical ALS patients. One possible explanation is that these individuals are genetically different, granting them a form of disease "resistance".

However, it appears that cases of ALS reversal are primarily documented in this specialized clinic. This does not mean that such cases do not exist elsewhere, but the diagnosis of ALS and, therefore, of ALS reversal is complicated. For example, it differs between countries in Europe, the United States, and Asia. More importantly, diagnoses vary considerably among doctors.

The problem is that we don’t fully understand what ALS is. Most agree it’s a phenotype that can result from many different causes—some genetic, others from exposure to neurotoxins, physical injury, or other factors.

An example of these variations in practice: the clinical study manager accepted people with primary muscular atrophy (PMA) into his study but PMA is not ALS.

Another issue is how to define “reversal.” Here, reversal was defined as an improvement of at least 4 points on the ALS Functional Rating Scale, maintained for at least 6 months. The ALSFRS-R scale is known to be flawed; it can show improvement simply because of the use of new assistive devices. A 2016 paper co-authored by this researcher stated that most of these “plateaus” and “reversals” are temporary: "ALS plateaus and small reversals are common, especially over brief intervals." https://pubmed.ncbi.nlm.nih.gov/26658909/

The new publication also states: "It is not yet clear if extremely rare “ALS reversals” suffer from typical ALS, or rather from another, yet undescribed disease mimicking ALS diagnostic criteria." https://pmc.ncbi.nlm.nih.gov/articles/PMC12419016/

The last year's study didn't just describe the phenomenon; it identified a specific gene, IGFBP7. It linked reversals to a noncoding variant near IGFBP7, which influences IGF-1 receptor activity. Since IGF-1 has long been suspected of having neuroprotective effects (it has been tested in past ALS clinical trials), this genetic link feels biologically plausible. Yet, more than one hundred genes are associated with ALS, especially SOD1, FUS, and C9orf72 (~9% of cases). These genes aren’t directly related to IGF, making it hard to think that patients with mutations in those genes could still experience reversals.

The authors did openly acknowledge the study’s limitations, which likely sparked discussion:

• The "Reversal" group included only 22 participants. This is a major limitation, and the results must be confirmed with larger groups.
• The study shows a strong genetic link, but it doesn’t prove that the IGFBP7 variant causes the reversals. It seems Professor Bedlack is now exploring this path: https://pubmed.ncbi.nlm.nih.gov/40944442/

Biogen, Roche, Takeda, and Vertex Pharmaceuticals have exited the AAV capsid field. Meanwhile, Pfizer has completely abandoned all work in gene therapy.

This is very unfortunate for the neurodegenerative disease field, where many familial cases could, in theory, be cured with such technologies.

Many gene therapies have received regulatory approval. Most of these approaches use adeno-associated viruses (AAVs) and lentiviruses for gene delivery, in vivo and ex vivo, respectively.

The scientific foundation is solid (we understand how to design vectors and deliver genetic payloads), but industrialization faces many bottlenecks. Manufacturing costs per patient remain very high—hundreds of thousands of dollars.

Since gene therapies primarily target rare diseases, the patient populations are small. Companies cannot rely solely on scaling to lower costs. After the initial cohort is treated, the market shrinks dramatically.

While academia can demonstrate that gene therapies work on a small scale, industry needs to prove that these therapies are reliable, scalable, safe, and financially sustainable—much higher standards. This explains why many promising academic results lead to companies retreating when confronted with the challenges of large-scale production and commercialization.

Alternatives such as mRNA, antisense therapies (ASO), and protein drugs offer different balances of feasibility, durability, safety, and economic viability.

Huntington’s Disease and C9orf72 ALS: Shared Mechanisms and Therapeutic Hopes

Approximately 70,000 people have been diagnosed with Huntington’s disease (HD) in the U.S. and Europe, with hundreds of thousands more at risk of inheriting the condition. Despite the clear genetic cause of HD, there are currently no approved therapies that delay onset or slow progression.

Both Huntington's disease and C9orf72-linked ALS, while clinically distinct, share a common hallmark: long, abnormal repetitions of DNA bases. The success of antisense oligonucleotides (ASOs) in spinal muscular atrophy (SMA, SMN1 gene) in 2017, followed by gene therapy in 2019, gave researchers confidence to pursue similar strategies in HD and C9orf72 ALS. Progress in treating one of these repeat expansion diseases may provide hope for others.

1. Genetic Basis

1.1 Huntington’s disease (HD)

HD is caused by an expanded CAG trinucleotide repeat in the HTT gene. - Normal alleles: up to approximately 26 repeats - Pathogenic threshold: 36 or more repeats

CAG encodes glutamine, leading to a mutant protein with an expanded polyglutamine (polyQ) tract. This toxic protein disrupts neuronal function and accumulates throughout the body, contributing not only to neurodegeneration but also to systemic issues like muscle atrophy, cardiac problems, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy.

1.2 C9orf72 ALS/FTD

C9orf72-related ALS and frontotemporal dementia (FTD) are caused by an expanded GGGGCC (G4C2) hexanucleotide repeat in the C9orf72 gene. - Normal alleles: up to approximately 30 repeats - Pathogenic alleles: hundreds to thousands

The expansion causes disease through several mechanisms: - Reduced C9orf72 protein levels - Formation of toxic RNA foci - Production of abnormal dipeptide repeat proteins via repeat-associated non-ATG (RAN) translation

1.3 Other repeat expansion diseases

• Spinocerebellar ataxias (SCAs) – many caused by CAG expansions
• Fragile X syndrome – CGG expansion in FMR1
• Myotonic dystrophy – CTG expansion in DMPK

2. Therapeutic Approaches: Shared Strategies

2.1 Antisense oligonucleotides (ASOs)

ASOs aim to reduce toxic transcripts. - HD: ASOs targeting HTT mRNA have reached clinical trials (e.g., Roche/Ionis). - C9orf72 ALS: ASOs targeting repeat-containing transcripts are in early-stage trials.

2.2 Gene silencing/editing

The most advanced approach in HD is uniQure’s AMT-130 gene therapy: - Uses an AAV vector to deliver microRNAs designed to silence mutant HTT. - Administered through MRI-guided stereotactic neurosurgery directly into the striatum. - Clinical trials (U.S. and Europe) are ongoing, with promising early results showing up to 75% slowing in disease progression in high-dose patients over 36 months.

These approaches are not yet cures, but they show that disease modification is possible. Advances in vector design (AAVs, lipid nanoparticles) are directly transferable to other repeat expansion disorders.

2.3 Targeting RNA structures

Small molecules that bind abnormal RNA structures (hairpins, G-quadruplexes) are under development for C9orf72 ALS and myotonic dystrophy, with potential extension to CAG-repeat disorders like HD.

2.4 Modulating protein homeostasis

Strategies to boost autophagy, proteasome activity, or molecular chaperones could reduce toxic protein aggregates in both HD and C9orf72 ALS.

3. Translating Progress Across Diseases

Research tools—such as assays for RNA foci, protein aggregation, and repeat instability—are shared across laboratories working on different repeat expansion disorders. Breakthroughs in one disease can therefore be rapidly tested in others.

Delivery challenges are also common: therapies must reach neurons in the brain and spinal cord. Advances in intrathecal ASO delivery or viral vector engineering benefit all disorders in this family.

In summary: Huntington’s disease and C9orf72 ALS/FTD are distinct conditions, but they share a unifying principle: DNA repeat expansions that disrupt RNA and protein homeostasis. Therapeutic strategies—including antisense oligonucleotides, RNA-targeting drugs, and gene-editing technologies—are broadly applicable across these diseases. Progress in one field accelerates progress in others, offering shared hope for patients facing these devastating neurodegenerative disorders.