The journal Science published an interesting article a few days ago. It concerns a fragment of RNA with promising properties. enter link description here

On the one hand, it appears to properly fold the TDP-43 proteins involved in ALS (it's a kind of chaperone molecule), and on the other hand, it could relocate these proteins to the cell nucleus.

If these results could be translated to humans, this would be the first drug capable of treating a large proportion of ALS patients. The approach is conceptually similar to that of antisense therapies, which provided the first truly effective drug against ALS, but which is only suitable for one or two percent of these patients.

This result stems from years of work involving numerous people and testing thousand candidate molecules.

A patent application has been filed, which, given the significant investment involved, demonstrates that the researchers have good hopes of being able to commercialize their expertise. Nevertheless, caution is advised.

What changes occur between elderly people with Alzheimer's disease and those who have developed cognitive resilience?

Recent work at the Netherlands Institute for Neuroscience compared brain tissue from healthy individuals, people with Alzheimer's disease, and people with Alzheimer's pathology but with intact cognitive function (resilient cases). The study provides a clearer picture of the behavior of immature neurons in these different conditions.

To study this phenomenon, the team used human brain tissue from the Netherlands Brain Bank, which collects and stores brain samples donated for research purposes. These samples included brains from control donors without brain pathology, from patients with Alzheimer's disease, and from people with Alzheimer's disease who did not develop dementia.

Identification of Immature Neurons in the Adult Brain

A crucial step was reliably identifying immature neurons (imNs) in adult human tissues. To validate these cells, researchers compared them to fetal hippocampal cells, where neurogenesis is well established.

Common Transcriptional Profile: Adult immature neurons (ImNs) exhibit gene expression profiles similar to those of fetal neuroblasts, confirming their identity as developing neurons. A subset of these cells expresses the OTOF gene, a marker observed in humans but absent from commonly used animal models, such as mice or macaques.

Using a targeted sampling approach focused on relevant hippocampal layers, the study detected a higher proportion of these cells than previously reported (approximately 12% of the dataset).

A long-standing question is whether these seemingly immature neurons are truly new or are instead older cells that have remained undifferentiated. Several observations support the hypothesis of a recent generation:

• Immature neurons (ImNs) exhibit high expression of genes related to DNA repair, mitochondrial function, and telomere maintenance—processes typically associated with young cells.

• Compared to neighboring mature neurons, these cells appear "younger," in terms of gene expression, than the chronological age of the donor.

• Immature neurons (ImNs) are more dependent on glycolysis, a metabolic change frequently observed in the early stages of cell differentiation.

• Unlike degenerating or identity-losing neurons, they exhibit limited expression of genes associated with inflammation or cell death.

Differences between Alzheimer's Disease and Resilience

The most relevant comparisons concern the differences between these cells according to the stage of the disease.

• In severe Alzheimer's disease (SAD), immature neurons exhibit reduced expression of key developmental markers (such as STMN1/2), increased pro-inflammatory signaling, and decreased activity of genes involved in DNA repair and amyloid regulation. Resilient individuals (RES), on the other hand, exhibit higher expression of genes such as CLU (clusterin) and PSAP (prosaposin), both associated with neuroprotection and resistance to damage from amyloid plaques.

• Healthy control individuals, for their part, exhibit a baseline expression profile, although some early alterations in specific subtypes of immature neurons are detectable even in the early stages of the pathology.

Intercellular Communication

A notable difference between the three population types lies in how immature neurons interact with their environment. In healthy, resilient brains, immature neurons participate in active signaling with other cell types, including microglia and mature neurons, whereas in Alzheimer's patients, this communication network is severely reduced, suggesting a breakdown in local cellular coordination.

A key observation is that the total number of immature neurons does not differ significantly between the groups. The main differences lie instead in their molecular state and their interactions.

This has led to a shift in the interpretation of the effects of neurogenesis in older adults. Rather than primarily replacing lost neurons, these immature cells could support the existing neuronal network, notably through signaling, metabolic support, or the modulation of inflammation. In this sense, their role is less a matter of quantity than of functional integration and cellular health.

Genes such as CLU and PSAP appear to be essential to this process, promoting survival and reducing vulnerability to pathological stress. Their high expression in resilient individuals suggests that maintaining protective programs within these cells could contribute to preserving cognitive function despite the presence of Alzheimer's disease.

Conclusion

This study confirms the hypothesis that the adult human hippocampus continues to harbor immature neurons with characteristics consistent with a recent generation. The crucial differences between Alzheimer's disease and cognitive resilience lie not simply in the number of these cells present, but in their function.

Alzheimer’s disease remains one of the hardest areas in drug development. One major reason is the behavior of amyloid-beta (Aβ), a peptide strongly associated with the disease, especially its 42-amino-acid form Aβ42.

Unlike many proteins targeted by conventional drugs, Aβ does not maintain one stable 3D structure. Instead, it behaves as an intrinsically disordered peptide, constantly shifting among many conformations. This makes it difficult to apply the usual “lock-and-key” approach of drug design, where a molecule is built to fit a well-defined binding pocket.

A recent paper by Morita, Maruyama and colleagues in Chemistry – A European Journal proposes a different strategy: rather than searching for a fixed pocket, the researchers use chirality-guided molecular recognition to bind a short sequence motif within Aβ42 and interfere with its aggregation.

Why amyloid-beta is difficult to drug

Aβ42 is a classic example of a target that resists standard medicinal chemistry.

Traditional small-molecule drugs work best when a protein has:

• a stable fold
• a persistent groove or pocket
• a clearly defined active site

Aβ42 has none of these features. Its pathological behavior comes from self-assembly into oligomers and fibrils, rather than from an enzyme-like function.

This is why many researchers describe intrinsically disordered proteins as hard to drug, even though the term “undruggable” is probably too absolute.

The challenge is therefore not simply “finding something that sticks,” but finding a molecule that selectively redirects or blocks a highly dynamic aggregation pathway.

What is actually new about the chirality idea?

The use of chirality itself is not new.

Researchers have studied D-peptides (mirror-image peptides made from D-amino acids) for years, including in Alzheimer’s research. D-peptide candidates such as RD2 already exist, and chirality has also been used to study Aβ uptake, aggregation, and membrane interactions.

So the novelty of this paper is more specific.

What appears genuinely new is the systematic design framework:

The authors first studied how short peptide sequences form stereocomplexes with their mirror images, identified the sequence features that favor this interaction, then used those rules to rationally design a D-peptide against the –FFAE– motif of Aβ42.

This moves the work beyond the older “try D-peptides and screen what works” approach.

The conceptual advance is the idea that mirror-image recognition can become a design principle, especially for intrinsically disordered proteins where fixed-structure targeting is difficult.

That broader framing may be more important than the Alzheimer’s angle alone.

Why the approach is scientifically interesting

The designed D-peptide inhibited Aβ42 fibril formation in vitro and reduced Aβ42-associated toxicity in neuronal-like cells. In the authors’ assays, it even outperformed RD2, an existing clinical-stage D-peptide comparator.

Several features make this attractive in principle:

1) It targets a sequence motif rather than a rigid structure

Because the interaction is based on sequence complementarity and stereochemistry, it may work even when the target peptide remains flexible.

That is a useful idea for intrinsically disordered proteins more broadly, including proteins implicated in Parkinson’s disease and some cancers.

2) D-peptides are protease-resistant

A practical advantage of D-amino-acid peptides is that most biological proteases evolved to degrade L-peptides.

This often gives D-peptides:

• longer half-life
• greater metabolic stability
• improved persistence in biological fluids

This is one reason mirror-image therapeutics have attracted long-standing interest.

3) It may reduce trial-and-error screening

Perhaps the most important long-term potential is methodological.

If stereocomplexation rules can be generalized, this could become a rational route to designing binders for disordered proteins, which is still a major unmet need in drug discovery.

Roadblocks before this becomes therapeutic

This remains an early proof-of-concept, and several major uncertainties remain.

Brain delivery is still a major challenge

A D-peptide that works in solution or cultured cells still needs to cross the blood–brain barrier.

This is one of the central bottlenecks in Alzheimer’s therapeutics, and the paper does not solve that translational problem.

Real Aβ biology is more complex than purified assays

Aβ42 in the brain does not exist as one clean species.

It transitions among:

• monomers
• soluble oligomers
• protofibrils
• mature fibrils
• membrane-associated forms

A binder optimized against one motif in vitro may behave differently in this far more heterogeneous environment.

Cell protection is not disease modification

The cell experiments are encouraging, but rescue of cultured neuronal-like cells is still very far from demonstrating efficacy in animals or humans.

Many anti-amyloid strategies have looked convincing at this stage and later failed in vivo.

Manufacturing and formulation remain nontrivial

D-peptides are chemically synthesizable, which is an advantage, but scaling highly pure sequences can still be expensive.

For CNS delivery, formulation requirements may further complicate development.

A broader perspective: why this may matter beyond Alzheimer’s

The most valuable part of this study may not be the immediate therapeutic claim.

Its broader significance is that it offers a general molecular-recognition strategy for intrinsically disordered proteins, a class of targets that remains difficult across neuroscience and oncology.

In that sense, the paper is less about “a near-term Alzheimer’s drug” and more about expanding the design toolbox for hard protein targets.

That is a meaningful contribution, even if the path to a medicine remains long.

Bottom line

This study should be seen as a carefully reasoned molecular design paper, not as evidence that Alzheimer’s treatment is about to change.

The real advance is not simply “using mirror-image chemistry,” since that field already exists. The more interesting step is the rule-based use of chirality to design sequence-targeting ligands for disordered proteins.

If that principle proves transferable, it could become useful well beyond amyloid-beta.

For now, it is best understood as a promising strategy at the chemistry and early cell-biology stage, with major delivery, validation, and translational hurdles still ahead.

When Japan's pharmaceutical regulators approved a new treatment for Amyotrophic Lateral Sclerosis (ALS) in September 2024, it marked a significant moment in the decades-long search for therapies that can slow this devastating disease. The drug, Rozebalamin®—a high-dose formulation of mecobalamin (vitamin B12)—represents an entirely different approach to treating ALS, and the clinical trial data suggests it may offer patients something precious: more time with meaningful function.

For decades, treatment options have been limited. Riluzole, approved in the 1990s, extends life by approximately two to three months but has minimal impact on day-to-day function. More recently, edaravone showed modest benefits but requires an intensive intravenous infusion schedule. The field has desperately needed options that make a tangible difference in how patients live.

Mecobalamin is nothing new—it's an active form of vitamin B12, long used at low doses to treat peripheral neuropathy. But in the 1990s, Japanese researchers began exploring whether dramatically higher doses—50 to 100 times the standard amount—might have neuroprotective effects in ALS.

The hypothesis centers on homocysteine, an amino acid that, at high levels, appears toxic to neurons. Mecobalamin acts as a coenzyme for methionine synthase, the enzyme that converts homocysteine to methionine. By lowering homocysteine levels, high-dose mecobalamin may protect motor neurons from damage. Additionally, through its role in methylation—a process essential for nucleic acid and protein metabolism—it may help repair nerve tissue.

Preclinical studies offered early promise. In Wobbler mice, an animal model of ALS, high-dose mecobalamin significantly slowed the decline in grip strength and increased motor neuron survival.

The road to approval wasn't straightforward. An initial Phase II/III trial (known as Trial 761) failed to meet its primary endpoint when looking at the general ALS population. However, researchers noticed something intriguing: patients who had been diagnosed early appeared to benefit. That observation led to the withdrawal of an initial application in 2015 and a redesigned study focusing specifically on early-stage patients.

The JETALS study was an investigator-initiated Phase III trial that enrolled patients within one year of their first ALS symptoms. Crucially, researchers also stratified participants by how rapidly their disease was progressing, focusing on "moderate progressors"—those losing one to two points on the standard ALS functional rating scale (ALSFRS-R) during a 12-week observation period.

The results, published in early 2026, were striking:

Over 16 weeks of treatment:

• Patients receiving high-dose mecobalamin (50 mg) saw their ALSFRS-R scores decline by an average of 2.7 points

• The placebo group declined by 4.6 points. This represents a 43% slowing of functional decline—a difference of approximately two points on the 48-point scale

• For the 90% of participants also taking riluzole, the benefit was even more pronounced: a 45% slowing of decline.

In ALS, where every point on the ALSFRS-R represents a concrete ability—using a pen, climbing stairs, swallowing safely—preserving two points over just four months translates directly into maintained quality of life.

Perhaps even more compelling were the long-term findings. Post-hoc analyses of patients who started treatment early suggested an extension in "event-free survival" (time until death or the need for permanent ventilation) of approximately 500 to 600 days. In a disease where existing drugs add months, gaining nearly two years is extraordinary.

Equally remarkable was the safety profile. The drug was well-tolerated, with side effects limited to minor issues like injection site pain, constipation, or rash—comparable to placebo. This stands in sharp contrast to many neurologic drugs that require balancing efficacy against toxicity. As one neurologist noted, achieving a 43% slowing of a fatal disease with the safety profile of a vitamin is something of a "holy grail."

The "early window" appears critical. The drug seems most effective when started within 12 months of symptom onset, before significant motor neuron loss has occurred. For patients further along in the disease course, the damaged nerves may be beyond rescue.

The JETALS trial enrolled a specific population, which matters for interpreting the results:

• Disease duration: Less than one year since first symptom

• Progression rate: Moderate (1-2 point decline on ALSFRS-R over 12 weeks)

• Physical status: Ambulatory, able to live with minimal assistance

• Lung function: Forced Vital Capacity greater than 60%

Both sporadic and familial ALS patients were included, provided they met established diagnostic criteria. The focus on "moderate progressors" reflects trial design considerations—patients who decline too slowly make it difficult to measure drug effects in a 16-week study, while those declining too rapidly may have disease too aggressive for any current therapy to slow measurably.

Rozebalamin® is not a cure. It slows decline but does not stop or reverse it. The benefits are most pronounced for those in early stages, and the evidence supports its use specifically in patients who are still progressing at a moderate rate.

Nevertheless, for a disease where treatment advances have been measured in incremental steps, this represents genuine progress. Japan's approval in 2024 has opened the door, and the published data in early 2026 provides the scientific community worldwide with a clear picture of what the drug can—and cannot—achieve.

Ongoing research will explore whether combination with other therapies might enhance benefits, and whether longer treatment periods yield even greater effects. For now, patients and clinicians have a new tool—one that works through a novel mechanism, offers meaningful slowing of functional loss, and does so with remarkable safety.

In the landscape of ALS therapeutics, that's worth paying attention to.

The reference article is available at: https://www.jstage.jst.go.jp/article/fpj/161/2/161_25066/_html/-char/ja

This study addresses a major debate regarding the causality of the C9ORF72 gene mutation in neurodegenerative diseases: does this mutation cause ALS and FTD via toxic RNA aggregates or toxic DPR proteins?

Traditionally considered distinct diseases, ALS and FTD share certain characteristics. In 2011, two research teams independently discovered that an abnormal repeat of the GGGGCC sequence in the C9orf72 gene is the most common genetic cause of ALS/FTD. In most people, this sequence is repeated between two and 20 times, but in some individuals, it can be repeated thousands of times. It is currently the most frequently observed mutation associated with ALS, far more common than SOD1, FUS, or TDP-43.

Ribonucleic acid (RNA) consists of a transient copy of a portion of DNA corresponding to one or more genes of a biological organism. mRNA is used by cells as an intermediary for protein synthesis. mRNA is a copy of DNA, comprising the coding region flanked by non-coding regions. It is synthesized as a precursor in the cell nucleus during a process called transcription. It then undergoes several maturation steps; some non-coding regions called introns may be excised during a process called splicing. The matured mRNA is exported to the cytoplasm where it is translated into protein by a ribosome. The information carried by mRNA consists of a series of codons, consecutive triplets of nucleotides, each of which codes for one amino acid of the corresponding protein. The sequence of these codons constitutes the gene itself, or cistron.

Normally, when a section of messenger RNA is converted into a protein, this section is delimited by a start codon and a stop codon. However, there is sometimes an abnormal conversion from an unconventional starting point, by translation of extended hexanucleotide repeats present in an intron of the C9orf72 gene, which produces short proteins called dipeptide repeat proteins (DPRs) that could be toxic.

However, the mechanism by which the expansion of the hexanucleotide repeat of the C9orf72 gene induces neurodegeneration remains poorly understood. An important question, therefore, is to determine whether it is the abnormal repeat of the GGGGCC sequence in the C9orf72 gene or the abnormal translation of the RNA of this gene that is toxic to neurons.

This study concludes that dipeptide repeat proteins (DPRs) are the main drivers of the disease, and not the RNA aggregates (foci).

Scientists have long struggled to separate these two factors, because DPRs are translated directly from the mutated RNA. To solve this problem, researchers used an ingenious gene-editing technique:

• Target: They identified a specific start codon (CUG) that triggers the translation of the toxic proteins.

• Modification: They replaced this CUG codon with CCG.

Result: The cell still produced the mutated RNA (and the resulting RNA foci), but it could no longer "read" the instructions necessary for the synthesis of the toxic DPR proteins. By testing this approach on mouse models of both diseases and on human patient stem cells (iPSCs), the team observed several crucial improvements:

• Behavior: Complete recovery of motor and cognitive deficits in mice.

• Brain health: Reduction of neuroinflammation and significant increase in neuronal survival.

• Biomarkers: Decreased levels of NfL (a protein released into the bloodstream upon neuronal death).

• Cellular pathology: Elimination of TDP-43 aggregates, a "waste" protein characteristic of ALS/FTD.

This discovery opens a new chapter for potential therapies. Instead of tackling the complex challenge of eliminating all the mutated C9ORF72 RNA (which may have other vital functions), we can now focus on strategies to specifically target and block the production of these toxic DPR proteins.

Here’s how this could lead to future treatments:

• CRISPR gene editing: The very technique used in this study—CRISPR base editing—could be harnessed for therapeutic purposes. Delivering a “molecular editor” to brain cells to change the critical CUG codon to CCG could be a one-time treatment that permanently prevents DPR synthesis. This would involve significant challenges in terms of delivery to the brain and ensuring specificity, but the potential is immense.

• Antisense oligonucleotides (ASOs): These custom-designed molecules are already used in other neurological disorders. ASOs could be developed to bind specifically to RNA at or near the CUG start codon, physically blocking the cellular machinery of its translation into DPR.

• Small molecule drugs: The pharmaceutical industry could search for small molecules capable of interfering with the RAN translation process itself, or of specifically targeting proteins involved in the initiation of DPR synthesis. This approach could be a more traditional, drug-analytical alternative.

A Promising Step Forward in Parkinson’s Disease Cell Therapy

There are few new approaches to alleviate Parkinson's disease symptoms. Most of them either consist of supplementing the brain with dopamine or introducing perturbations deep in the brain. As with other neurodegenerative diseases, a regenerative approach is potentially much more attractive. A recent report from the First Affiliated Hospital of the University of Science and Technology of China (USTC) has drawn considerable attention in the field of Parkinson’s disease (PD) research. Led by neurosurgeon Shi Jiong, the team has developed an iPSC-based cell therapy that may mark a meaningful step toward regenerative treatment for PD.

A Highly Efficient Stem Cell–Based Approach

The therapy relies on induced pluripotent stem cells (iPSCs) that are reprogrammed from adult donor cells. These iPSCs are then differentiated into dopamine-producing neural progenitors, the type of cells that gradually disappear in Parkinson’s disease. One of the notable achievements of the USTC team is its >80% efficiency in generating these dopaminergic neurons — a rate well above the standard reported by other groups.

The resulting product, called NCR201 and developed by Nuwacell, is now being evaluated in a Phase I clinical trial. The early results are striking. One participant, who initially had severe motor disability (UPDRS score 62), improved to near-normal function (score 28) within three months of the implant procedure. The researchers describe this as a “functional cure,” while emphasizing that longer follow-up is essential before drawing final conclusions.

A Precise Surgical Method Built for Cell Survival

Delivering fragile stem-cell–derived progenitors into deep brain structures requires meticulous technique. The USTC team uses a combination of three elements designed to maximize precision while minimizing risk:

1. Stereotactic Cell Implantation Stereotaxy provides a three-dimensional coordinate system that allows surgeons to target very small structures with sub-millimeter accuracy. For PD, the target is the putamen, part of the striatum, where dopamine normally acts to regulate movement.
2. MRI Guidance Instead of relying solely on pre-operative imaging, the team performs the procedure with intra-operative MRI. This allows real-time visualization of the putamen, the cannula tip, and even the distribution of the infused cell suspension. Because brain tissue can shift during surgery, real-time imaging helps ensure that the cells are released exactly where intended.
3. Bilateral, Low-Dose Implantation Parkinson’s disease affects both sides of the brain, so the procedure involves implantation into both putamina. The “low-dose” designation reflects the specific cell dose tested in this early trial arm and the minimally invasive nature of the robot-assisted approach.

Together, these components aim to increase both safety (reducing the risk of hemorrhage or misplacement) and efficacy (ensuring cells reach the optimal anatomical location). The dramatic clinical outcome reported in the case example likely reflects this high degree of precision.

What NCR201 Actually Is: Dopaminergic Progenitor Cells from iPSCs

The therapy uses iPSC-derived dopaminergic progenitor cells, a format designed to balance safety and function: • iPSCs: Adult donor cells are reprogrammed into pluripotent cells that can be expanded indefinitely. Using a well-characterized, allogeneic donor line allows for consistency and avoids ethical issues tied to fetal tissue. • Dopaminergic progenitors: Instead of transplanting fully mature neurons, clinicians implant precursor cells that are already committed to the dopamine-producing lineage. This reduces the chance of tumor formation and allows the cells to complete their maturation inside the patient’s brain, where they can better integrate into existing circuits.

The therapeutic goal is straightforward: provide a renewable source of dopamine in the striatum, ideally restoring motor function in a sustained, biological way.

Known Challenges in Early-Stage Stem Cell Trials

As promising as the first results are, Phase I trials are designed to evaluate safety, and several key risks remain central to ongoing monitoring:

• Tumor formation from any remaining undifferentiated iPSCs.

• Immune rejection, since NCR201 is not patient-specific and may require immunosuppressive medication.

• Long-term survival and stable function of the transplanted cells, which must endure for years in the diseased brain environment.

• Manufacturing consistency, an ongoing challenge for living cell products.

Other groups worldwide are pursuing similar strategies. Their approach uses donor cells selected for immunological compatibility and a specialized cell-sorting method to enhance safety. Autologous trials, in which each patient receives cells derived from their own tissue, are also under development, though they are slower and more expensive to produce.

Could This Become a Commercial Therapy?

The commercial potential is substantial, especially if long-term data confirm that a single transplant can restore durable motor function. Such an outcome would represent a major advance compared with current PD medications, which provide symptomatic relief but do not modify the course of the disease.

That said, the path to approval is lengthy: • 10–15 years is a realistic estimate before this type of therapy could reach the market. • Phase II and III trials will need to show benefit in larger and more diverse patient populations, with long-term follow-up to rule out late complications. • Manufacturing and surgical delivery will remain complex and costly, at least initially. Scaling these procedures in a way that ensures accessibility will require continued innovation.

Outlook

The early success of the USTC team’s cell-replacement trial is an encouraging sign for regenerative approaches to Parkinson’s disease. It combines a high-quality iPSC-derived cell product with a precise, imaging-guided surgical technique. While many questions remain — especially concerning longevity, safety, and scalability — the work adds meaningful momentum to an area of research that could, over time, change the way PD is treated.

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.