Differences in disease treatment between countries are evidence that medicine is not an exact science (if there ever was one). For example, it has been shown in certain cancers that crossing a state border can offer a better chance of survival. The article that is the subject of this post takes us to China in Taizhou, in the Zhejiang province.

It seems that in Asia (China, Japan) we talk about Parkinson's disease with dementia, as distinct from Lewy body disease. This dementia is managed with donepezil, which is not done in the West where this drug is rather used for Alzheimer's disease.

Donepezil is one of those drugs with unpleasant side effects that sometimes lead to patients abandoning them.

Murine NGF (nerve growth factor) has been licensed in China since 2003. It appears to improve patient outcomes for several nervous system diseases. This is important because few drugs can treat nervous system diseases. Unfortunately, research and clinical use outside of China are limited.

Doctors in Taizhou wanted to investigate the clinical efficacy of donepezil combined with nerve growth factor (NGF) in the treatment of Parkinson's disease (PD) dementia and its potential impact on serum adiponectin (APN) and soluble tumor necrosis factor receptor-1 (sTNFR-1) levels.

Clinical data from 140 PD patients treated at Taizhou People's Hospital from March 2021 to December 2023 were retrospectively analyzed. Patients were grouped according to the treatment received. Patients receiving donepezil alone (n = 68) were in the Donepezil group, and patients treated with a combination of donepezil and NGF (n = 72) were assigned to the Donepezil and NGF group.

The overall efficacy of the combination therapy was superior to that of donepezil alone treatment. The authors focused on adiponectin, an adipocytokine, i.e. a molecule produced by adipose tissue, which is involved, among other things, in the regulation of lipid and glucose metabolism. Adiponectin modulates inflammatory cascades by modifying the action and production of inflammatory cytokines, but the link between adiponectin and Parkinson's disease is not obvious unless we consider that Parkinson's disease is due to a metabolic disorder. The relationship with the soluble tumor necrosis factor receptor (sTNFR) is even less obvious. Nothing in the article explains why these two molecules were studied.

The serum APN levels after treatment in the donepezil and NGF group were significantly higher than in the donepezil alone group, while the sTNFR-1 level was significantly lower. There was no significant difference in the incidence of adverse events between the two groups.

In conclusion, the combined treatment regimen of donepezil and NGF is more effective than donepezil monotherapy in improving cognitive function, neurological function, and severity of the condition in patients with Parkinson's disease with dementia, and is associated with suppression of the inflammatory response without a significant increase in the incidence of adverse events. Hopefully, these studies will be considered in the Western world.

Here is a paper that outlines a new theory on the cause of Alzheimer's disease with implications for Parkinson's disease as well as ALS.

This is just speculation, based on almost only one fact: The expression of many genes is involved in this disease, so it would imply a global deregulation of the cellular machinery. Unfortunately, as usual in biology, this is a purely qualitative theory and, therefore, susceptible to many possibly contradictory interpretations. However, it is a theory that sees many neurodegenerative diseases as belonging to a spectrum rather than as distinct diseases. I endorse this point of view. Alzheimer's disease research has produced many hypotheses over the years, including cholinergic, inflammatory, viral, mitochondrial, tau, and amyloid. However, none of these hypotheses have led to treatments that can stop or reverse the disease. This leads to a search for new theories to explain these failures. But this may be because interventions occur too late in the disease progression, with brain damage irreparable and compensatory mechanisms saturated.

Most publications ignore physiology, such as the importance of drainage in the cerebral lymphatic channels that have been discovered in recent years. This publication is no exception to this unfortunate trend, it is a discussion of the functioning of a cell in general, not even a brain cell like a neuron or an astrocyte, and the theory is even mostly not specific to humans or mammals, which still leaves one very skeptical. In this publication, the authors suggest that a disrupted nucleocytoplasmic transport system, linked to the formation of stress granules (SG), plays a central role. Cellular stress itself can have multiple causes independent of each other. There is no clear explanation why a general blockage of the cell would specifically lead to the appearance of beta-amyloid in Alzheimer's disease, nor that of alpha-synuclein in Parkinson's disease or TDP-43 in ALS.

In this model, cellular stress triggers SGs, which disrupt the movement of molecules between the nucleus and the cytoplasm, affecting RNA transport, chromatin accessibility, and alternative splicing. These changes lead to synaptic dysfunction, metabolic disorders, protein processing defects, and ultimately cell death. When this process propagates to brain regions, it results in clinical Alzheimer's disease.

The authors present a multistep mechanism linking SGs, NCT dysfunction, and amyloid propagation: * SG formation disrupts nucleocytoplasmic transport, altering gene expression and RNA localization. * Aβ clearance is decreased due to impaired lysosomal function, reduced proteostasis, and disrupted Aβ export. * Aβ production may increase via impaired APP processing. * Seeding and spreading of Aβ aggregates are facilitated by exosome dysregulation and chaperone sequestration. * Glial activation and BBB dysfunction further enhance Aβ diffusion in the brain.

The mention of ALS, FTD, and other conditions with similar transport disruptions strengthens the model's plausibility by showing how dysfunction of nucleocytoplasmic transport is implicated in multiple diseases.

Eukaryotic cells regulate the movement of molecules between the nucleus and the cytoplasm through nuclear pore complexes (NPCs), which are composed of nucleoporins. This transport is controlled by importins, exportins, and the protein Ran, which provides the energy for molecular movement.

Stress granules (SGs) are nonmembranous cytoplasmic structures that form in response to cellular stress, typically through phosphorylation of eukaryotic initiation factor 2 (eIF2α). During transient stress, SGs help cells recover, but during chronic stress, such as in Alzheimer's disease (AD), SGs abnormally persist and sequester key molecules, disrupting transcription and nucleocytoplasmic transport.

Disruption of nucleocytoplasmic transport in Alzheimer's disease (AD) was first reported in 2006, when cytoplasmic accumulation of nuclear transport factor 2 (NTF2) was observed in hippocampal neurons, even before the formation of neurofibrillary tangles (NFTs). This suggests that dysfunction of the transport system occurs early in the progression of AD. Analysis of gene expression data shows similar transport-related disruptions in tangle-bearing and non-tangle-bearing neurons.

Similar disruptions are observed in ALS, FTD, Huntington's disease, and even in non-neurological diseases such as cancer and heart failure. However, the specific transport disruptions vary by disease, likely due to different patterns of SG sequestration.

Some neurons maintain normal expression of the transport system and show enrichment in translational and neuronal function pathways, while others, with altered expression of the transport system, display stress-related pathways and deficits in mitochondrial function and metabolism. These findings are consistent with in vitro studies, suggesting that AD progresses along a continuum at the cellular level, ultimately leading to widespread neuronal dysfunction and clinical symptoms.

Conclusion The text suggests a causal role for SGs and transport dysfunction in AD, but much of the available supporting evidence comes from in vitro studies or studies of related diseases (e.g., ALS, FTD). The available direct in vivo evidence demonstrating SG-mediated pathology in AD patients is still limited.

Although the text discusses tau tangles and Aβ, their role appears secondary to SGs. Since amyloid and tau pathology remain at the core of AD research and therapeutic efforts, their relative downplaying constitutes a potential weakness.

The proposed model is primarily based on molecular and cellular studies, with little reference to clinical data.

Usually, I strive to find articles that have some interest in patients. This means eliminating the countless articles about cell culture that bring little new knowledge in basic science and have zero interest in pre-clinical research.

Yet here is one about cell culture that may retain some interest. It's about a type of karyopherin that transports protein molecules from the cell's cytoplasm to the nucleus. It does so by binding to specific recognition sequences, called nuclear localization sequences (NLS).

Upon stress, several karyopherin proteins stop shuttling between the nucleus and the cytoplasm and are sequestered in stress granules. Everyone interested in ALS knows this is an important topic in neurodegenerative diseases. Neurodegenerative proteinopathies are characterized by progressive cell loss that is preceded by the mislocalization and aberrant accumulation of proteins prone to aggregation in the cell's cytoplasm. Despite their different physiological functions, disease-related proteins include tau, α-synuclein, TAR DNA binding protein-43, fused in sarcoma, and mutant huntingtin. Recent advances into the underlying pathogenic mechanisms have associated mislocalization and aberrant accumulation of disease-related proteins with defective nucleocytoplasmic transport and its mediators called karyopherins. These studies identified karyopherin abnormalities in amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer’s disease, and synucleinopathies including Parkinson’s disease and dementia with Lewy bodies, that range from altered expression levels to the subcellular mislocalization and aggregation of karyopherin α and β proteins.

In addition to their classical function in nuclear import and export, karyopherins can also act as chaperones by shielding aggregation-prone proteins against misfolding, accumulation, and irreversible phase-transition into insoluble aggregates. Karyopherin abnormalities can, therefore, be both the cause and consequence of protein mislocalization and aggregate formation in degenerative proteinopathies.

A new study suggests that the upregulation of two karyopherins might improve cell health in C9orf72.

Hexanucleotide repeat expansions in C9orf72 are the primary genetic mutation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), collectively referred to as C9-ALS/FTD. The resulting dipeptide repeat (DPR) proteins, such as poly(proline-arginine) (polyPR), generated from G4C2 repeat expansions, have been shown to be highly toxic.

To investigate the cellular localization of PR20, a polyPR protein, it was labeled with fluorescein isothiocyanate (FITC). Notably, several cell lines survived PR20 treatment by sequestering it in the cytoplasm. However, treatment with JQ-1 or Ivermectin (Iver) translocated PR20 into the nucleus, leading to cell death.

Mechanistically, the interaction between KPNA2/KPNB1 and PR20 in the cytoplasm prevented PR20 from entering the cell nucleus. Genetic silencing of KPNA2/KPNB1 converted PR20-resistant cells into PR20-sensitive cells. Specifically, JQ1 treatment decreased KPNA2/KPNB1 protein levels, allowing PR20 to enter the nucleus.

Conversely, overexpressing KPNA2 or KPNB1 effectively blocked cell death induced by co-treatment with JQ-1 and PR20. The authors' findings suggest that the upregulation of KPNA2/KPNB1 protects cells from PR20 toxicity.

Pharmacological targeting of karyopherins represents a promising new strategy for therapeutic intervention in neurodegenerative diseases. Yet by the time patients are diagnosed, a significant number of neurons are already lost, while the remaining functional ones are doomed to degenerate over time due to the lack of efficient treatments. So, it's important not to exaggerate the benefits of drugs in those diseases.

Several compounds targeting karyopherins are already in clinical trials to treat specific forms of cancer and viral infections, so it might be less costly to retarget these drugs toward neurodegenerative diseases than it is for entirely new drugs.

One of the most devastating for of amyotrophic lateral sclerosis (ALS) is the loss of control of the muscles involved in speech and swallowing, which is called "bulbar onset". Early detection of changes during or after an ALS diagnosis could pave the way for interventions that improve quality of life, but conventional assessments often rely on subjective observation.

Indeed, surface electromyography observes the reaction of muscles that are excited by an electric current. This observation is subjective, it involves interpreting electrical signals by identifying patterns that are not obvious because they are fleeting and non-standardized. This observation depends heavily on the placement of the needles, but above all, from this observation the practitioner deduces the good or bad functioning of the lower and upper motor neurons. I am not a doctor, just a retired engineer, but I find that these deductions of the functioning of motor neurons from surface electromyography make absolutely no sense, no logic. Yet the majority of ALS diagnoses are made this way!

Furthermore, this approach is poorly adapted to bulbar involvement. Also, a slightly more standardized method of interpreting surface electromyography adapted to bulbar involvement would be welcome. A recent study renovates surface electromyography by automatically recording and interpreting the electrical activity of jaw muscles. The authors focused on three key muscles involved in jaw movement (the anterior temporal, the masseter, and the anterior belly of the digastric) by recording their activity while participants performed speech tasks. By applying the principles of network morphology, they showed that these subtle disturbances in the flow of communication between jaw muscles created a map of how these muscles coordinate with each other.

The study looked at three groups: ALS patients with overt bulbar symptoms, those in an earlier “prodromal” phase without overt symptoms, and healthy controls. Using sophisticated graph-based analysis, the researchers examined how muscle connectivity differed between these groups and whether these changes could serve as early warning signs of bulbar dysfunction.

The results were striking. Even for prodromal patients, this method highlights subtle disruptions in the flow of communication between jaw muscles. As the disease progressed, some features of the network continued to deteriorate, while others appeared to stagnate. Crucially, these network features correlated with measurable changes in jaw movement, reinforcing the idea that ALS changes not only the strength of muscles but also how they work together.

To further their findings, the researchers used machine learning models, and training algorithms to distinguish ALS patients from healthy individuals based solely on their muscle networks. The models performed well, suggesting that the technique could one day serve as an objective, data-driven tool to diagnose ALS earlier and more accurately than current methods.

However, moving this research from the lab to clinical practice will require several steps. Larger, more diverse studies are needed to confirm that the method reliably identifies ALS while distinguishing it from other speech-impairing conditions. To be widely used, the method must also be accepted by practitioners, who like many specialists are gradually being replaced by more reliable tools. To avoid being devalued, they will need to shift their service offerings toward greater personalization and the ability to interpret not raw results, but more sophisticated information.

Nevertheless, the study represents a significant step forward. By listening more closely to the hidden rhythms of muscle coordination, researchers have found a new way to detect muscle changes in ALS, which could help clinicians stay ahead of a disease that so often eludes early diagnosis.

This is a short post about this publication with an interesting title.

I thought it was about the acute anxiety of carers when their loved one could not eat anymore, actually, it is about how doctors in British hospitals manage patients who could not take their medication orally.

The alternatives are either a soluble medication, a topical patch, or a nasogastric tube.

I wonder if there is not a more urgent problem for patients that could not swallow, than taking their medication.

For once, we are going to talk about an article about Huntington's disease. Huntington's disease (sometimes called Huntington's chorea) is a rare hereditary disease that results in neurological degeneration causing significant motor, cognitive, and psychiatric disorders, and progressing to the loss of autonomy and then death. This disease occurs in adults aged between 35 and 50 on average. The progression of the disease follows a rhythm and a form that varies greatly from one individual to another.

The genetic abnormality that causes Huntington's disease is a greater than normal increase (20 times) of the repetition of three nucleotides (C, A, and G - called the CAG codon or triplet) within the HTT gene encoding the huntingtin protein. This blog focuses on three neurodegenerative diseases, ALS (sometimes called Charcot's disease or Lou Gehrig's disease), Parkinson's disease, or Alzheimer's disease. But in fact, it is only in books that these diseases are clearly categorized, in reality, we distinguish multiple subtypes to each of these categorizations and moreover, these diseases share characteristics both between themselves and with other neurodegenerative diseases.

A variant of ALS (C9orf72) closely resembles Huntington's disease in some aspects because it too is characterized by repeat expansions of a gene, C9orf72. Repeat expansions of the C9orf72 gene are responsible for about 40% of genetic ALS and 25% of genetic FTD.

The article we are discussing today focuses on the genetic and molecular mechanisms underlying Huntington's disease (HD), with a particular emphasis on the dynamics of CAG repeat expansions in the huntingtin (HTT) gene.

It explores the implications for the pathogenesis and therapeutics of HD. Although ALS is not cited by the authors, this paper has implications for that disease as well as for about 30 others.

An expansion of CAG triplet causes Huntington's disease repeats in the HTT gene. Normal alleles have 15 to 30 CAGs; disease-causing alleles have 36 or more. Longer CAG repeats correlate with earlier onset.

Scientists identified the progression of CAG repeat expansion with age by analyzing somatic mosaicism, or the variability in CAG repeat lengths between different cells within an individual. This variability increases over time, and the progression of CAG repeat length has been linked to cell-specific processes that cause expansions as individuals age.

The authors found that HTT alleles are not inherently toxic, but become harmful after somatic expansion exceeds approximately 150 repeats. This toxicity results in asynchronous and rapid neuronal decline, challenging the understanding of Huntington’s disease as a slowly progressive disease. They measured somatic repeat expansion over time in individual neurons from donors of different ages. They found that early-phase expansions (e.g., from 40 to 80 CAG repeats) were slow and stochastic, taking decades, while later expansions (e.g., from 80 to 150 repeats) occurred more rapidly. They then analyzed genetic markers and DNA repair mechanisms associated with repeat instability, such as those involving DNA mismatch repair (MMR) proteins (e.g., MSH3, PMS1). Variants in these genes have been shown to influence the rate of somatic instability. The progression of CAG repeat expansion is driven by errors in DNA replication, repair, and maintenance, particularly in neurons. Key mechanisms include:

Striatal projection neurons, the cells most affected by Huntington’s disease, exhibit higher levels of somatic instability than other cell types. This may be due to their unique transcriptional and metabolic profiles, which make them more susceptible to DNA damage and inefficient repair.

Expansion dynamics have been categorized into phases: - Phase A (36–80 repeats): Slow and stochastic over decades. - Phase B (80–150 repeats): Faster and more predictable. - Phase C (>150 repeats): Gene expression changes begin, leading to cellular dysfunction. Toxicity threshold: Neurons derepress other genes (e.g., CDKN2A/B) and eventually die.

These findings highlight how somatic mosaicism and age-related repeat expansions are central to the pathogenesis of Huntington’s disease and provide a framework for understanding similar processes in other repeat expansion disorders.

The somatic expansion mechanism may extend to other repeat expansion disorders, such as myotonic dystrophy or some forms of spinocerebellar ataxia.

The C9orf72 variant in ALS involves a hexanucleotide repeat expansion (GGGGCC) in a noncoding gene region. Although distinct from the CAG repeats in the Huntington’s disease coding region, there are notable parallels. As in Huntington’s disease, somatic instability of the repeat expansion has been observed in ALS C9orf72. The degree of mosaicism may influence disease onset and progression. C9orf72 expansions lead to toxic RNA foci and dipeptide repeat (DPR) proteins, leading to neuronal dysfunction and death. This reflects Huntington’s disease idea that toxicity only occurs after substantial repeat expansion. In ALS, motor neurons are selectively vulnerable. As in Huntington’s disease, the specific cell types affected may result from unique somatic instability dynamics.

Therapeutic potential: This work in Huntington’s disease suggests that modulation of DNA repair pathways (e.g., MSH3) may stabilize nucleotide repeats, thereby delaying toxicity.

It's a bit sad that scientists studying FTD think of themself as "dementia scientists" while scientists studying ALS or Parkinson's disease think they belong to a motor disorders category and motor neurons specialists for ALS scientists, while many neurodegenerative diseases share a lot of molecular and physiologic characteristics. At least these cases are often those of aged people and they involve mislocated and misfolded protein aggregates.

So many scientists from the Memory and Aging Center at the University of California, were motivated to study the impact of age on neurodegenerative diseases:

• They tell that age is the biggest risk factor for dementia, which is a way to present aging as a cause of neurodegenerative diseases, not simply a comorbidity.
• Most dementia cases (>75%) involve multiple types of brain pathologies, which implies again that those pathologies are not diseases in the same sense as communicable diseases where usually there is a single pathogen and removing this pathogen more or less (not always) restore health.
• Previous animal experiments showed that exchanging blood between young and old animals could affect brain aging (called "heterochronic blood experiments"). This is a controversial topic as some ultra-rich people already buy young blood of unclear origin. Identifying the detrimental substances and those that are beneficial would help human society as a whole.
• While individual blood factors had been identified in animal studies, their relevance to human disease wasn't well understood

This study involved the direct examination of persons in two cohorts: A longitudinal study of people with genetic frontotemporal dementia (FTD) and healthy controls. A cross-sectional study of people with sporadic Alzheimer's disease and controls.

• Discovery Cohort (ALLFTD Study): 119 people with FTD genetic mutations (37 MAPT, 33 GRN, 49 C9orf72) 78 healthy controls without mutations This was a longitudinal study (participants were followed over time) Participants had on average 3 annual evaluations (ranging from 1-7 visits) About half (52) of the mutation carriers were asymptomatic at the beginning of the study.

• Replication Cohort (Stanford ADRC): 35 people with Alzheimer's disease 56 clinically normal older adults This was a cross-sectional study (participants were NOT followed over time)

For both groups, the scientists collected: - Cerebrospinal fluid (CSF) through lumbar punctures - Comprehensive cognitive tests - Functional assessments (rated by caregivers) - Blood or CSF samples for NfL (a marker of neurodegeneration)

The scientists identified five specific proteins from previous animal studies: - Could cross the blood-brain barrier - Were measurable in human samples - Had shown effects on brain aging

These proteins included: Three "pro-aging" factors: CCL11, CCL2, B2M Two "pro-youthful" factors: CSF2 and BGLAP

They found that people with FTD mutations had lower levels of "rejuvenation proteins". Higher levels of these proteins were associated with slower disease progression The protective effect was seen across multiple cognitive domains. The effect was similar regardless of which specific FTD mutation people had

Similar protective associations were found in Alzheimer's disease. Higher levels of these proteins were associated with better cognitive performance and functional status. The effect was particularly strong for memory performance.

• CCL11 is a small cytokine belonging to the CC chemokine family. CCL11 selectively recruits eosinophils by inducing their chemotaxis, and therefore, is implicated in allergic responses. Increased CCL11 levels in blood plasma are associated with aging. Exposing young mice to CCL11 or the blood plasma of older mice decreases their neurogenesis and cognitive performance on behavioral tasks.
• CCL2, another cytokine, is implicated in pathogeneses of several diseases characterized by monocytes (a type of leukocyte or white blood cell) infiltrates, such as psoriasis, rheumatoid arthritis, and atherosclerosis
• B2M is a component of MHC class I molecules. MHC class I function is to display peptide fragments of proteins from within the cell to cytotoxic T cells. Systemic B2M accumulating in aging blood promotes age-related cognitive dysfunction and impaired neurogenesis. In addition, it promotes beta-amyloid aggregation and neurotoxicity in models of Alzheimer’s disease.
• CSF2 is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells, and fibroblasts, that functions as a cytokine.
• Osteocalcin, also known as (BGLAP), is a protein hormone found in bone. Numerous recent studies have revealed bidirectional crosstalk between the brain (and Alzheimer's disease) and bone health.

The publication does not mechanistically explain these "pro-aging" and "pro-youthful" factors. It may suggest that it pays to have a low inflammation level and to be physically active. The results appear relatively reliable because the scientists found similar effects in two different types of dementia. The effects were seen across multiple measures (cognitive, functional, and biological markers).

This research could impact drug development in several ways: - It suggests targeting multiple proteins simultaneously might be more effective than single-target approaches - It identifies specific proteins that could be therapeutic targets - It demonstrates these effects in humans, making it more likely to translate into effective treatments - The proteins are measurable in the blood, which could make treatment monitoring easier and safer than the very intrusive CSF sampling.

While not directly studied, this research could be relevant to ALS because ALS shares some biological mechanisms with FTD (they're often considered part of the same disease spectrum).

The research suggests a new paradigm for treating neurodegenerative diseases by targeting multiple age-related factors simultaneously, rather than focusing on single disease-specific pathologies. This could be particularly relevant for diseases like ALS where multiple mechanisms contribute to disease progression.

Preclinical studies are performed on a number of organisms, which scientists call "animal models of the disease." This concept is very vague and can involve everything from immortalized cancer cells to nematodes or fish. The most serious work is done on several standardized and commercial mouse models. This makes it possible in theory to compare work between laboratories, although this remains difficult in practice. However, commercial mouse models of disease are expensive and are almost useless for diseases like ALS, because the nervous system of mice is very different from the human nervous system. However, in preclinical studies, scientists look for clues that a drug might be useful, but it is not yet possible to prove that a drug will be effective in humans. One of the best things they can do at this stage is to show that a drug has a positive effect on several unrelated commercial animal models. The endoplasmic reticulum (ER) is an important organelle in cells that is involved in protein conformation. This step occurs after protein synthesis by ribosomes and after conformation, the new protein will be sent to its final destination by the Golgi apparatus. Protein conformation requires energy, so when disease occurs, the ER may not be able to properly conform the new proteins.

The accumulation of unfolded proteins leads to ER stress, followed by an adaptive response via activation of the unfolded protein response (UPR). Since folded proteins require energy, the unfolded protein response significantly slows down the production of new proteins. This is a way to cope with temporary stressful events, but it is not sustainable, as a cell that does not produce proteins is in a kind of stasis and will die quickly. Indeed, prolonged cellular stress activates apoptosis signaling leading to cell death.

Several studies have shown that impaired endoplasmic reticulum (ER) proteostasis is a pathogenic feature of ALS/FTD. Several drugs targeting the UPR in ALS have been proposed (GSK2606414, ISRIB, Guanabenz, Sephin1, Trazodone, KIRA), but none seem to be effective in ALS at this point.

There are different strategies, one is to stop the prolonged deleterious UPR in the hope that somehow the stressor has disappeared and the cell is healthy again. Another, on the contrary, tries to force an unfolded protein response state on all cells in the hope that the cell will be able to clear the backlog of accumulated misfolded proteins. However, the involvement of the UPR and the mechanisms by which ER stress contributes to pathogenesis are not entirely clear and can have contrasting or even opposing effects. Contributing to this complexity is that the UPR is actually several mechanisms.

The transcription factor XBP1s has several roles, one of them being that of regulator of the unfolded protein response. In a new publication, scientists provide evidence of suboptimal activation of the UPR in mouse models of ALS/FTD under experimental ER stress.

They designed a genetic therapy so that nervous system cells in ALS/FTD mouse models express the active form of XBP1 (XBP1s). XBP1s expression improved motor performance and extended lifespan in SOD1 mutant mice, associated with reduced protein aggregation.

It is important to note that AAV-XBP1 administration also attenuated disease progression in mouse models of TDP-43 and C9orf72 pathogenesis. As noted at the beginning of this text, most preclinical work in a single animal model is a bit suspect, especially when the animal model is not standardized but performed by administering a chemical that affects the nervous system.

ALS SOD1 disease is probably very different from TDP-43 and C9orf72 diseases. As SOD1 is an anti-oxidant, a mutated SOD1 protein probably protect less neurons from metabolism by-products. TDP-43 protein has many roles but one is to repair DNA in pluripotent stem cell-derived motor neurons. Most ALS patients have misfolded, aggregated fragments of TDP-43 in cell's cytosol which is weird as normally TDP-43 should be in cell's nucleus where it could repair DNA. C9orf72 is different again, in this disease the cellular ribosomes produce the wrong proteins from correct RNA, a so-called frameshift effect.

It is not clear how an XBP1s drug could benefit these three variants of ALS. However, if this is confirmed in humans, it would be good news because today, only one drug benefits ALS patients (Tofersen), but it benefits less than 1% of them. Having a drug that would benefit most patients would be extraordinary.

But we are not there yet, a first step would be to understand the mechanism of action of this drug in ALS