There are many articles on statins and ALS, and in general the results show that statin use does not influence the progression of ALS.

Statins are commonly used to manage cholesterol levels and reduce the risk of cardiovascular disease, but their safety in amyotrophic lateral sclerosis (ALS) has long been questioned by both patients and their caregivers. Since the mid-1990s, weight loss has been identified as a contributing factor for patients with ALS, leading to a 7.7-fold increased risk of death. Many individuals worry that statins may accelerate the progression of ALS or exacerbate symptoms, and reports from drug monitoring systems suggest a potential link between a diagnosis of ALS and statin use; however, these reports have yet to be validated in epidemiological studies. In contrast, findings from more recent studies indicate that high LDL cholesterol and elevated LDL/high-density lipoprotein ratios occurring well before the onset of ALS may be associated with an increased risk of developing the disease.

A new Norwegian study on this topic confirms that statin use does not impact the progression of ALS.

https://pubmed.ncbi.nlm.nih.gov/40034089/

The researchers analyzed data from four Norwegian health surveys spanning the years from 1972 to 2003. They linked these surveys to national registries to track ALS diagnoses, mortality, and medication use. Specifically, they examined whether statin use before and after an ALS diagnosis influenced survival time.

The researchers included 524 ALS patients in the analysis. They compared statin use before and after diagnosis and adjusted for various factors, including age, sex, smoking status, BMI, cholesterol levels, and use of riluzole (the main ALS drug).

Their work found no association between statin use and ALS survival. Interestingly, 21% of ALS patients stopped taking statins in the year before their diagnosis. This group had a poorer prognosis, perhaps because of worsening general health, but the fact they stopped using statins did not appear to have improved ALS survival.

The study therefore suggests that routinely stopping statins in ALS patients is not necessary. Since statins do not appear to have a negative impact on survival, stopping them solely because of an ALS diagnosis may deprive patients of their cardiovascular benefits.

Two recent studies highlight the complex interplay between metabolic dysregulation and ALS progression.

The first study investigated energy balance and glucose control in TAR DNA-binding protein 43 (TDP-43)Q331K mice, which serve as a model for ALS, during both the early and late symptomatic stages of the disease. It suggests the presence of compensatory mechanisms that regulate glucose metabolism differently in this form of ALS. Thus, targeting metabolic pathways, such as insulin signaling and oxidative stress, could provide new therapeutic approaches for ALS.

The etiology of ALS is complex, involving mechanisms such as neuroinflammation, protein aggregation, and energy metabolism dysfunction. The origin of hypermetabolism in amyotrophic lateral sclerosis remains unknown; however, metabolic perturbations in skeletal muscle may be a determining factor, including an increase in the expression of pyruvate dehydrogenase kinase 4 (PDK4), which plays a central role in regulating the oxidation of glucose.

Both sporadic and familial ALS cases commonly exhibit metabolic disturbances, including weight loss, increased resting energy expenditure, and hypermetabolism, which are associated with poorer disease outcomes. Interestingly, a higher body mass index (BMI) at disease onset is linked to increased survival, and high-calorie, high-fat diets have shown some benefits in ALS patients and mouse models, suggesting that metabolic interventions could influence disease progression.

Insulin resistance has been implicated in the progression of ALS. Some studies indicate that diabetes mellitus increases the risk of ALS, while others suggest that type 2 diabetes may delay the onset of the disease. This discrepancy highlights the need for further research into how energy homeostasis and insulin signaling are affected in ALS. Previous studies on SOD1G93A mice, a model of familial ALS, revealed increased energy expenditure and enhanced glucose uptake through insulin-independent pathways, along with glucagon intolerance.

The discrepancy between studies may stem from differences in tissue-specific glucose uptake, as ALS patients exhibit increased glucose uptake in denervated muscles but decreased uptake in the central nervous system.

Building on these findings, the first study investigated metabolic perturbations in the TDP-43Q331K mouse model, which mimics the neuropathological and metabolic hallmarks of human ALS, including TDP-43 pathology, a common feature in both familial and sporadic ALS.

TDP-43Q331K mice exhibited significantly increased daily energy expenditure (DEE) from the early symptomatic stages of the disease. This hypermetabolism was accompanied by a transient increase in food intake, which helped maintain fat mass initially but was insufficient in later stages, leading to fat mass reduction.

During the later stages of the disease, TDP-43Q331K mice showed improved glucose clearance, independent of insulin. Despite reduced circulating glucagon levels, these mice maintained normal fasting blood glucose levels, suggesting alternative mechanisms for glucose regulation.

Unlike SOD1G93A mice, TDP-43Q331K mice did not exhibit insulin or glucagon intolerance. Insulin sensitivity remained unchanged, and while glucagon levels were reduced, the mice maintained normal blood glucose levels, indicating the involvement of other regulatory mechanisms.

Consistent with other ALS models, TDP-43Q331K mice experienced a reduction in lean mass during both early and late disease stages. Regression analysis confirmed that the increased energy expenditure was independent of changes in body mass.

The TDP-43Q331K mutation drives significant metabolic changes, including hypermetabolism and altered glucose uptake, which are not observed with wild-type TDP-43.

The increased glucose uptake in later disease stages is insulin-independent, highlighting the activation of alternative metabolic pathways in response to the disease.

The ability of TDP-43Q331K mice to maintain fasting blood glucose levels despite reduced glucagon suggests the existence of compensatory mechanisms that regulate glucose metabolism differently in this ALS model.

• The second study, a phase 2a clinical trial, explored the pharmacodynamic response of trimetazidine, a partial fatty acid oxidation inhibitor, on oxidative stress markers and energy expenditure in amyotrophic lateral sclerosis. This publication highlights how it's difficult and inconclusive to conduct an ALS clinical trial as twenty-one participants received trimetazidine but only 19 completed the treatment period. While trimetazidine is a well known drug, usually well tolerated, the assessment of energy expenditure may have been uncomfortable. While there were 57 adverse events, the conclusion was, as usual, that the drug was well tolerated! While the publication recounts that trimetazidine was beneficial for patients (this is not a phase III trial), for me the results section does not show conclusive results. For example, the results improved only during the wash-out period.

The authors tell that the on-treatment period may have been too short, or the sample size too small to detect a disease-relevant change, if one exists. Moreover, in this study, they simply used the approved dose for angina pectoris. Therefore, it remains unclear whether dosing was appropriate and whether a different dose would have resulted in more substantial reductions. Finally, the response in the oxidative stress markers may also be explained by external factors that influence metabolism, such as concomitant medication use and smoking, which cannot be completely ruled out in this uncontrolled study.

While the study was limited by its short duration and lack of a control group, the findings suggest that trimetazidine may help mitigate the hypermetabolic state in ALS and improve disease outcomes. Larger, randomized controlled trials are needed to confirm these results and determine the optimal dosing regimen.

These findings suggest that targeting metabolic pathways, such as insulin signaling and oxidative stress, could offer new therapeutic avenues for ALS. Future research should focus on understanding the underlying mechanisms of metabolic dysregulation, exploring the potential of antidiabetic agents, and conducting larger clinical trials to evaluate the efficacy of metabolic modulators like trimetazidine in ALS patients.

SUMO (Small Ubiquitin-like Modifier) proteins are a family of small proteins that are attached to and detached from other proteins in cells to modify their function. This process is called SUMOylation. SUMOylation is to signal to other cellular mechanisms that the protein attached must be processed. There are at least 4 SUMO isoforms in humans; SUMO-1, SUMO-2, SUMO-3, and SUMO-4. SUMO proteins are involved in a variety of cellular processes, such as nuclear transport, transcriptional regulation, apoptosis, and protein stability. Transactive response DNA-binding protein 43 (TDP-43) is a nuclear RNA binding protein (RBP) involved in RNA metabolism. TDP-43 has a high propensity to aggregate because of its low solubility in cells and in vitro. The aggregation propensity of TDP-43 is increased by ALS/FTD-linked mutations and upon exposure to stress and has been observed in patients with C9orf72 hexanucleotide repeat expansion, the most common genetic cause of sporadic and familial.

Stress conditions trigger the accumulation of TDP-43 in cytosolic stress granules. The role of stress granules in modulating TDP-43 aggregation is ambiguous. Functionally, SUMO2/3-ylation has been shown to maintain stress granules in a dynamic state: SUMOylation inhibition impairs stress granule disassembly, but the underlying mechanism is still unknown.

In this paper, the authors report that upon oxidative stress (induced by sodium arsenite), TDP-43 becomes modified by SUMO2/3 protein chains and moves from the nucleus to cytoplasmic stress granules. This conclusion is probably also valid for other stress conditions, so this study is of great interest. When researchers blocked SUMOylation, TDP-43 became less mobile within the cell, stress granules took longer to disassemble, and TDP-43 was more likely to form insoluble aggregates. Yet this is not a study on humans, the authors used various immortal cell lines, motor neuron cells, and Caenorhabditis elegans worms. Furthermore, the authors used genetic therapies to infect cells to express or repress PIAS4. This is easy to do in vitro but most probably hard to achieve in a seriously ill patient.

Because TDP-43 aggregation is central to familial and sporadic ALS, approaches aimed at preventing TDP-43 aggregation hold promise for future treatments. How cells control TDP-43 aggregation is poorly understood. Modifiers of TDP-43 solubility include molecular chaperones and posttranslational modifications. Besides ubiquitination, which is a key posttranslational modification required to clear aggregation-prone proteins, phosphorylation of TDP-43 is emerging as a protective response to counteract its misfolding. Phosphorylation of TDP-43 decreases its assembly into condensates and suppresses TDP-43 aggregation and toxicity.

Under normal growth conditions, cells prefer to modify proteins with SUMO1, while during cellular stress, SUMO2 and SUMO3 are usually conjugated in the form of SUMO2/3 chains (referred to as SUMO2/3-ylation). TDP-43 when SUMO1-ylated stays in the nucleus, does not aggregate in the cytoplasm, and its splicing activity is modified.

Using experiments in cells, the authors show that conjugation of TDP-43 with SUMO2/3 coincides with stress granule assembly. Pharmacological inhibition of TDP-43 SUMO2/3-ylation triggers TDP-43 aggregation inside stress granules.

E3 SUMO-protein ligase PIAS4 is one of several protein inhibitors of activated STAT (PIAS) proteins. PIAS proteins act as transcriptional co-regulators with at least 60 different proteins to either activate or repress transcription. The transcription factors STAT, NF-κB, p73, and p53 are among the many proteins that PIAS interacts with. PIAS4 has been shown to recruit proteins to the site of the DNA damage and promote repair.

The authors found that PIAS4 helps attach SUMO2/3 to TDP-43. - PIAS4-mediated SUMO2/3-ylation increases the solubility of TDP-43 and prevents its aggregation in the cytoplasm. - Depleting PIAS4 leads to TDP-43 aggregation In motor neurons from the human spinal cord in familial ALS cases with TDP-43 and C9orf72 mutations, reduced cytoplasmic PIAS4 correlates with increased TDP-43 aggregates.

RNA binding appears to compete with SUMOylation: When cells are not subjected to stress, TDP-43 is mainly localized inside the nucleus, binding with high affinity to RNA. When TDP-43 is bound to RNA, it's less likely to be SUMOylated. When cellular RNA levels are low, there's increased SUMO2/3 modification This suggests SUMOylation may be a protective mechanism when TDP-43 isn't bound to RNA

The authors conclude that modification with SUMO2/3 chains maintains the solubility of RNA-free TDP-43 during stress.

There are many studies on reducing TDP-43 aggregates in ALS, but this one looks much more sophisticated than the previous ones. Yet this is mostly an in-vitro study. Long pre-clinical studies must be conducted on mammals to verify if a simple and safe agonist of PIAS4 (which does not exist today) could improve the health of ALS patients.

A few years ago I tried to model the course of ALS using SBML, a systems biology tool now abandoned by scientists.

At the time there was no model of ALS, but since then there have been very interesting attempts, for example, this one:enter link description here

However, few scientists and almost no doctors use models based on differential equations today, we live in an era where statistical models are all the rage. In addition, biology as it is practiced is essentially qualitative, which makes it not very suitable for modeling and which attracts the mockery of "soft science", because by nature it is not capable of making consistent predictions. One only has to look at the colossal failure rate of clinical trials to be convinced of this.

The publication reviewed in this post focuses on understanding the regulatory dynamics of amyotrophic lateral sclerosis (ALS) using the widely used SOD1-G93A transgenic mouse model.

ALS is a multifactorial disease, and previous studies have often focused on isolated aspects rather than its complex and interconnected nature.

The study suggests that ALS regulation may be hypervigilant, meaning that the system overcorrects in response to stress, leading to damaging oscillatory behavior that contributes to disease progression. The study uses an innovative and integrative framework to model the regulatory dynamics of wild-type (WT) and SOD1-G93A ALS mice. The models are based on first-order ordinary differential equations (ODEs) that describe how the system output evolves over time. The research uses dynamic meta-analysis to synthesize experimental data from the literature and parameter optimization based on genetic algorithms to infer missing data. Indeed, to build a model, data are needed and here these are obtained from results reported in the literature on SOD1-G93A ALS mouse models.

The study shows that SOD1-G93A mice with ALS exhibit unstable physiological regulation, characterized by oscillatory behavior due to hypervigilant regulation. This instability intensifies near disease onset and worsens with progression.

Computational models of the physiological dynamics of wild-type (WT) and transgenic SOD1-G93A mice were constructed: a WT mouse model to simulate normal homeostasis and a SOD1-G93A ALS model to simulate the dynamics of ALS pathology and their response to treatments in silico. The model simulates the functional molecular mechanisms of apoptosis, metal chelation, energetics, excitotoxicity, inflammation, oxidative stress, and proteomics using data curated from published SOD1-G93A mouse experiments. Time-course measures of disease progression (rotarod, grip strength, body weight) were used to validate the results from the literature.

The health of untreated SOD1-G93A ALS mouse models cannot be maintained due to oscillatory instability. The onset and magnitude of homeostatic instability corresponded with disease onset and progression. Oscillations are associated with high feedback gain due to hypervigilant regulation.

Multiple virtual treatments combined were able to stabilize the dynamics of SOD1-G93A ALS mice to near-normal WT homeostasis. However, treatment timing and effect size are critical for stabilization to match therapeutic success. The most common unidirectional stabilizing treatment was pro-proteomics, while the most common bidirectional stabilizing treatment was energy consumption and anti-apoptosis. The authors cite anti-apoptosis factors such as caspase-9 inhibitor, caspase-3 inhibitor, Bax inhibitor, and Bcl-2 homolog BCL-XL.

A major drawback is that this type of ALS only affects less than 2% of ALS cases and if it is still largely overrepresented in the literature, it is because the association of this type of mutation with ALS is historically the first to have been discovered during the boom in genetics and for almost 15 years no other association has been found.

Another important point is that we do not know what mechanisms cause this disease, or even if it is a single disease. Models of this type therefore make many assumptions and their results are less robust than they appear.

The study highlights the multifactorial nature of ALS, which involves various molecular mechanisms, such as apoptosis, bioenergetics, excitotoxicity, inflammation, oxidative stress, and proteomics. These mechanisms are interconnected, and their dysregulation contributes to disease progression.

The study also explores the potential of combination therapies to stabilize the regulatory dynamics of ALS. Previous studies focusing on single therapeutic targets have often been inadequate, but combination treatments have shown success in the management of other complex diseases such as cancer, COVID-19, and HIV. The study suggests that precisely timed combination therapies targeting multiple pathways may be necessary to achieve meaningful results in ALS.

Code and data are not available at the indicated Github address.

The authors acknowledge that first-order feedback models may not fully capture the complexity of biological systems, including phenomena such as bistability and hysteresis. But for now, we are still in the prehistory of biological systems modeling, the field needs to be developed before focusing on its imperfections.

I fear that this publication will go way over the heads of health professionals working in the field of ALS.

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.

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