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• W4365795766 abstract "Introduction of Fas apoptosis inhibitory molecule (FAIM): FAIM was originally discovered in FAS-resistant mouse primary B lymphocytes in 1999, and was thought of as a FAS-apoptosis inhibitor based on overexpression studies (Schneider et al., 1999). FAIM is an approximately 20 kDa intracellular protein, but a subsequent study identified an alternatively spliced form, termed FAIM-Long (L), which has 22 additional amino acids at the N-terminus (Zhong et al., 2001). Thus, the originally identified FAIM was renamed FAIM-Short (S). FAIM is also termed FAIM1 in some publicly available gene/genome databases. Although two other gene products were confusingly termed FAIM2 (also termed lifeguard) and FAIM3 (also termed TOSO), neither FAIM2 nor FAIM3 are related to FAIM-S and FAIM-L in terms of physiological functions or gene/protein homology. FAIM-S is ubiquitously expressed in the body, but FAIM-L is expressed almost exclusively in the brain and testis (Zhong et al., 2001). Overexpression studies using B lymphocytes showed that FAIM inhibits FAS-mediated apoptosis presumably by enhancing NF-κB activation (Schneider et al., 1999; Kaku and Rothstein, 2009a, b). However, the physiological role of FAIM (hereafter FAIM indicates both FAIM-S and FAIM-L) was unknown for many years, partly because no abnormality was detected in FAIM-deficient mice. It was not until our recent studies that we discovered FAIM-deficient cells are more susceptible to cellular stress (Kaku and Rothstein, 2020). In retrospect, its role might have previously been obscured by the lack of stress in vivarium mouse life. Our recent findings: FAIM is involved in proteostasis: Recently, we found an unexpected but more physiologically relevant function of FAIM. FAIM-deficient cells/tissues are less equipped to handle cellular stress as evidenced by aggressive accumulation of insoluble ubiquitinated protein aggregates upon induction of heat or oxidative stress (Kaku and Rothstein, 2020). Stress-induced cellular dysfunction is often associated with the appearance of disordered and dysfunctional proteins that must be disposed of to maintain cellular viability. Stress-induced disordered proteins are tagged with ubiquitin for intracellular degradation via the proteasome system and the autophagic pathway. If the load of stress-induced, ubiquitinated proteins exceeds the abilities of disposal mechanisms, these proteins may accumulate in an insoluble form. This aggregation of proteins into fibrillar high-molecular-weight species is a pathological hallmark of numerous human neurodegenerative disorders, including Alzheimer’s disease (AD). In AD, extracellular amyloid-β (Aβ) plaques and intracellular tau tangles are believed to cause neuronal cell death in affected regions of AD brains. We recently discovered that FAIM is recruited to a complex containing ubiquitinated proteins in the event of cellular stress to prevent further aggregation (Kaku and Rothstein, 2020). Therefore, we will discuss in this perspective the newfound role of FAIM as a protein aggregate inhibitor, its connection to the underlying pathology of AD, and its potential as a disease-modifying therapy. Paradigm shift in the physiological FAIM function: Given that FAS-mediated apoptosis is normal in FAIM-deficient cells (Kaku and Rothstein, 2020), it is possible that the observed inhibition of FAS-mediated apoptosis by FAIM-overexpression (Schneider et al., 1999) was simply an artifact of overexpression due to protein/gene dosage imbalances that altered biological outcomes as opposed to a direct effect of FAIM itself. Further, the recent finding that FAIM-deficient cells accumulate protein aggregates supports the more physiologically relevant role of FAIM as a protein aggregate inhibitor (Kaku and Rothstein, 2020). It might be that FAIM’s original function during evolution was the inhibitory effect on protein aggregation, not FAS-mediated apoptosis. This is evidenced by the origin and evolutionary history of the faim and FAS-apoptosis-related genes. According to the recently updated gene database (https://useast.ensembl.org/index.html), the faim gene arose in choanoflagellates over 600 million years ago and displays extremely high evolutionary conservation throughout holozoan species from choanoflagellates to humans, which is more similar to the degree of evolutionary conservation seen in housekeeping genes (Figure 1). Furthermore, apoptosis-related genes, including the fas and fasl genes, are much less conserved and evolved much later (Figure 1). Thus, we have concluded that FAIM’s real physiological function is not inhibition of FAS-apoptosis but inhibition of protein aggregation to protect cells from stress-induced cell death. This conclusion is further supported by the recent observation that protein aggregates spontaneously form in aged FAIM-deficient retinas and that many photoreceptor cells within these retinas subsequently died. Although the exact mechanism of photoreceptor cell death was not investigated, those that died had the greatest amount of protein aggregates (Sires et al., 2021).Figure 1: Identities of FAIM amino acid sequence to homo sapiens FAIM-S during evolution based on Ensembl database (% homology).The faim gene evolved much earlier than apoptosis-related genes. The in silico analysis indicates the existence of faim genes in the premetazoan genomes of single-celled choanoflagellates like M.brevicollis and S.rosetta, which is one of the closest living relatives of animals and a progenitor of metazoan life that first evolved over 600 million years ago. S.rosetta contains only 9411 genes, out of which two faim genes were found. This evidence suggests that the original/major roles of FAIM might not be apoptosis-regulation. A.queenslandica: Amphimedon queenslandica; C.elegans: Caenorhabditis elegans; D.rerio: Danio rerio; FAIM: Fas apoptosis inhibitory molecule; FAS-L: Fas ligand; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HPRT: hypoxanthine phosphoribosyltransferase. Created with Keynote software.The relationship between FAIM and Alzheimer’s disease: As previously mentioned, the accumulation of abnormal proteins in AD brains leads to the formation of extracellular Aβ plaques and intracellular tau tangles, which subsequently results in cell death. We have recently found that recombinant human FAIM proteins prevent aggregation of Aβ (Kaku et al., 2021) and tau (unpublished observation) in an in vitro cell-free system. Similarly, FAIM protein prevents aggregation of superoxide dismutase 1 G93A, which is associated with amyotrophic lateral sclerosis, in an in vitro cell-free system (Kaku et al., 2020). These data imply that FAIM is sufficient to inhibit protein aggregation without any other cellular components that typically contribute to proteostasis, including elements of the proteasome and autophagic pathways. Therefore, FAIM possesses intrinsic chaperone activity similar to that of heat shock proteins (HSPs). Although we identified collaborative activity, co-localization, and structural similarities between FAIM and small HSPs (sHSPs), FAIM is not homologous to any HSPs (Kaku et al., 2022). Given this distinction, it is not surprising that FAIM possesses an additional, unique ability not found in sHSPs to solubilize pre-formed protein aggregates. FAIM can disaggregate pre-formed Aβ and superoxide dismutase 1 aggregates (Kaku et al., 2020, 2021). In addition to FAIM’s protein aggregation preventing capabilities, this solubilizing/disaggregase activity will add to its potential to be an effective disease-modifying therapy for multiple stages of AD pathology. In contrast, HSPs may have some drawbacks as therapeutic agents. For example, overexpression of HSPs was observed in some types of cancers (Wu et al., 2017). The enhanced activity of HSPs leads to tumorigenesis and metastasis and renders resistance to radiation and chemotherapy (Wu et al., 2017). Therefore, modulating FAIM activity may have an advantage over HSPs and may lead to rationally designed therapies for AD without causing severe adverse effects, such as tumorigenesis. In the brain, FAIM-S is expressed in astrocytes, microglia, and neurons. FAIM-L is only expressed in neurons but at higher levels than FAIM-S. An association between AD pathology and FAIM expression has been reported: FAIM-L expression was impaired in the hippocampus of AD patients, especially in the late BRAAK stages, but FAIM-S expression was comparable to healthy controls (Carriba et al., 2015). This observation implies that the levels of FAIM-L expression are inversely correlated with those of pathogenic Aβ and tau species. Given that FAIM antagonizes Aβ (Kaku et al., 2021) and tau fibrils (unpublished observation), we hypothesize that low/no FAIM-L expression may directly lead to more aggressive protein aggregation in AD patients rather than just act as a marker of AD progression. The unsatisfactory outcomes of current AD treatments: The current standard of treatment for AD is acetylcholinesterase inhibitors, such as donepezil, rivastigmine, and galantamine. This class of drugs was developed in response to the cholinergic hypothesis of neurodegeneration, which suggests that loss of acetylcholine producing neurons, particularly in the basal forebrain contributes significantly to the cognitive decline observed in AD (Breijyeh and Karaman, 2020). The N-methyl-D-aspartate receptor antagonist, memantine, is another drug commonly used in the treatment of AD, most often as an adjunct therapy to an acetylcholinesterase inhibitor for patients with moderate to severe disease. It was developed in response to the excitotoxicity hypothesis of neurodegeneration, which suggests that overstimulation of N-methyl-D-aspartate receptors by glutamate leads to an abnormal level of Ca2+ influx and subsequently, neuronal cell death (Breijyeh and Karaman, 2020). However, both drug classes only target the symptoms of AD. Because they do not address the underlying pathology, they do not have a significant effect on disease progression. Even when used in combination, they have shown only modest improvement in cognition and ability to perform activities of daily living (Chen et al., 2017). The monoclonal antibodies, aducanumab and lecanemab, which target pathogenic Aβ species characteristic of AD, were recently approved by the Food and Drug Administration with the hope that this new form of therapy would provide greater benefit given that it addresses the underlying pathology of AD. While both have proven to be effective in reducing the amount of pathogenic Aβ species, it is yet to be determined if there is any clinical benefit to this (Knopman and Perlmutter, 2021). In addition, several contraindications exclude certain individuals from receiving this treatment safely. For example, it is advised that patients at high risk for central nervous system bleeds should not be given aducanumab due to frequently observed cerebral hemorrhage following its administration (Knopman and Perlmutter, 2021). This renders a large portion of the Alzheimer’s population ineligible because a significant number of individuals within this age group are on long-term anticoagulant and/or antiplatelet therapy for comorbid conditions. While stimulation of an inflammatory response by antibodies is largely what permits the clearance of pathogenic Aβ species, occasionally an excessive response is triggered, resulting in life-threatening side effects, including cerebral hemorrhage as previously mentioned, and brain swelling (Figure 2A). This unpredictable response is due to the interaction between the Fc region of antibodies and microglia (Jeong et al., 2022; Withington and Turner, 2022).Figure 2: Potential future disease-modifying therapies for Alzheimer’s disease.(A) Single-molecule therapy using anti-Aβ or -tau antibodies to target either Aβ or tau. (B) Single-molecule therapy using FAIM activity to target both Aβ and tau simultaneously. (C) Combination therapy using anti-Aβ or -tau antibodies and FAIM activity to target multiple pathogenic Aβ or tau species. The prediction of FAIM structure is performed by AlphaFold. Aβ: Amyloid-β; FAIM: Fas apoptosis inhibitory molecule; FcR: Fc receptor. Created with Keynote software.The potential of FAIM as a disease-modifying therapy for AD: Given the pitfalls of current treatment options, there is a need for a new type of therapy that addresses the underlying pathology of AD in a way that translates into clinically significant results and confers a minimal side effect profile so as not exclude a large portion of the Alzheimer’s population based on the presence of other extremely prevalent medical factors that would render the treatment unsafe. We propose that, if FAIM can be translated into a deliverable form of therapy, or if small compounds capable of enhancing FAIM expression/activity are discovered, then it alone or in combination with current treatment has the potential to meet this need. Although which activators/repressors regulate FAIM transcription in human neurons remains unexplored, knowledge of the critical factors regulating FAIM expression will help screen compounds for enhancing FAIM expression to combat AD pathogenesis in the future. While monoclonal antibody therapies have been successful in removing pathogenic protein species, perhaps they confer only partial benefit at best because irreversible neuronal cell death has already occurred even though some neural network dysfunction induced by pathogenic Aβ species is reversible (Yuan et al., 2022). Given the impact of pathogenic species on neuron function and the difficulty in undoing it, it would seem that the ideal treatment would prevent the formation of Aβ plaques and tau tangles in the first place rather than retroactively removing them once a potentially irreparable amount of damage has already been done. We have shown that FAIM possesses the ability to prevent aggregation of both Aβ (Kaku et al., 2021) and tau fibrils (unpublished observation). This unique ability to target both species simultaneously makes it a more superior candidate for future treatment than those that target just one or the other given that both Aβ and tau species contribute to neurotoxicity (Figure 2B). FAIM’s preventative capabilities might suggest that patients would benefit most if treatment is initiated in the early stages of the disease, potentially requiring the use of early detection methods or clearly defined criteria based on early presenting symptoms that would assist in the determination of eligibility. However, we hypothesize that FAIM will confer clinically significant benefit regardless of which stage of the disease a patient is at when it is initiated. We hope that FAIM will slow disease progression from the point of therapy initiation onward. In addition to administering FAIM protein as a single molecule, we propose that a combination therapy of both FAIM and antibodies might be more clinically beneficial than FAIM alone (Figure 2C). We predict that targeting pathogenic protein species with multiple mechanisms will eliminate the aggregates more efficiently. Combination therapy is not an uncommon practice in the treatment of other disease processes, and given that all single-molecule AD therapies to date have not been satisfactory, it may be necessary to combine FAIM with another therapeutic agent for optimal results. Further, it is possible that the addition of FAIM would allow for a reduction in antibody dosage below that of the current single-administration therapies, thus reducing the probability of neuroinflammation-derived side effects, such as brain swelling and hemorrhage. FAIM itself is unlikely to elicit these side effects given that it is a protein naturally expressed by neurons and because it lacks the problematic Fc portion. Conclusion: Recent studies suggest that the physiologic function of FAIM is the inhibition of protein aggregation rather than the inhibition of FAS-mediated apoptosis as originally thought. The aggregation of pathogenic protein species is the underlying cause of many neurodegenerative diseases, including AD, which is characterized by Aβ plaques and tau tangles. It was recently discovered that FAIM antagonizes both Aβ and tau aggregation. Given this finding, there is hope that FAIM may replace or work in concert with current treatments, such as AChE inhibitors, which only target symptoms, and monoclonal antibody therapies, which are flawed in efficacy and side effects. FAIM will likely cause very few side effects, if any, because it is a protein naturally produced in the human brain and does not have the pro-inflammatory Fc region characteristic of antibodies. We propose that FAIM has the potential to become a disease-modifying therapy for AD either alone or with the help of anti-Aβ or -tau antibodies. This work was supported by the Pilot Research Project grant awarded by the Western Michigan University Homer Stryker M.D. School of Medicine, and Public Health Service grant AG072148 awarded by the National Institutes of Health (to HK). C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y" @default.
• W4365795766 created "2023-04-16" @default.
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• W4365795766 date "2023-04-20" @default.
• W4365795766 modified "2023-09-25" @default.
• W4365795766 title "Newfound physiological function of FAIM protein offers hope of novel disease-modifying therapy for Alzheimer’s disease" @default.
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