FAIM Is a Non-redundant Defender of Cellular Viability in the Face of Heat and Oxidative Stress and Interferes With Accumulation of Stress-Induced Protein Aggregates

Kaku, Hiroaki; Rothstein, Thomas L.

doi:10.3389/fmolb.2020.00032

Cited by 15 publications

(14 citation statements)

References 40 publications

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“…We previously showed ubiquitinated protein aggregates induced by cellular stress and mutant SOD1 aggregates accumulate in FAIM-deficient cells ( Kaku et al, 2020 ; Kaku and Rothstein, 2020 ). To assess the role FAIM plays in prevention of Aβ aggregation, we employed an APP-overexpression system using Neuro 2A cells, a mouse neuroblastoma.…”

Section: Resultsmentioning

confidence: 99%

“…Given that FAIM protein prevented and solubilized Aβ fibrils, we suggest the novel hypothesis that low/no FAIM expression might be pathogenically linked to more rapid, aggressive, overwhelming Aβ fibrillization in AD patients rather than simply functioning as a marker of AD progression. Furthermore, we previously showed that oxidative stress, applied in vivo to intact animals, produces increased protein aggregates in FAIM-deficient mice ( Kaku and Rothstein, 2020 ). Previous reports suggest that oxidative stress is linked to neurodegenerative diseases, presumably due to accumulation of toxic protein aggregates triggered by protein oxidation ( Butterfield and Kanski, 2001 ; Chong et al, 2005 ; Chen et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

“…Guide RNA (gRNA) sequences for mouse faim gene were designed using a CRISPR target design tool 1 in order to target the exon after the start codon as previously described ( Kaku and Rothstein, 2020 ). Briefly, designed DNA oligo nucleotides were ligated into pSpCas9(BB)-2A-GFP (PX458) vector (Addgene plasmid #48138, a gift from Feng Zhang) at the Bpi1 (Bbs1) restriction enzyme sites using the “Golden Gate” cloning strategy.…”

Section: Methodsmentioning

confidence: 99%

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Fas Apoptosis Inhibitory Molecule Blocks and Dissolves Pathological Amyloid-β Species

Kaku

Ludlow²,

Gutknecht³

et al. 2021

Front. Mol. Neurosci.

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A number of neurodegenerative diseases are associated with the accumulation of misfolded proteins, including Alzheimer’s disease (AD). In AD, misfolded proteins such as tau and amyloid-β (Aβ) form pathological insoluble deposits. It is hypothesized that molecules capable of dissolving such protein aggregates might reverse disease progression and improve the lives of afflicted AD patients. Here we report new functions of the highly conserved mammalian protein, Fas Apoptosis Inhibitory Molecule (FAIM). We found that FAIM-deficient Neuro 2A cells accumulate Aβ oligomers/fibrils. We further found that recombinant human FAIM prevents the generation of pathologic Aβ oligomers and fibrils in a cell-free system, suggesting that FAIM functions without any additional cellular components. More importantly, recombinant human FAIM disaggregates and solubilizes established Aβ fibrils. Our results identify a previously unknown, completely novel candidate for understanding and treating irremediable, irreversible, and unrelenting neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Fas Apoptosis Inhibitory Molecule Blocks and Dissolves Pathological Amyloid-β Species

Kaku

Ludlow²,

Gutknecht³

et al. 2021

Front. Mol. Neurosci.

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“…Among these, FAIM (Fas apoptosis inhibitory molecule) was first identified as a negative regulator of Fas signaling ( Schneider et al, 1999 ). It was later found to play multifaceted roles in other physiological processes such as the protective or deleterious effects of TNFα in neurodegenerative disorders ( Carriba et al, 2015 ), regulating axon-selective pruning, hippocampal long-term depression (LTD) ( Martinez-Marmol et al, 2016 ) and opposition to stress-induced accumulation of protein aggregates ( Kaku and Rothstein, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…In Parkinson’s disease, the expression of FAIM-L was found to be reduced in midbrain dopaminergic neurons after trophic factor deprivation, as well as to sensitize them to Fas-induced cell death ( Yu et al, 2008 ). Recent findings also show that FAIM could play a role in Amyotrophic Lateral Sclerosis inhibiting the aggregation of mutant SOD1, suggesting that FAIM participates in maintaining cell homeostasis ( Kaku and Rothstein, 2020 ). Kaku et al (2020) also described that FAIM is recruited to cellular stress-induced ubiquitinated proteins, and the levels of stress-induced protein aggregates are much greater in FAIM-deficient cell lines.…”

Section: Introductionmentioning

confidence: 99%

FAIM Is Regulated by MiR-206, MiR-1-3p and MiR-133b

Coccia

Masanas

López‐Soriano

et al. 2020

Front. Cell Dev. Biol.

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Apoptosis plays an important role during development, control of tissue homeostasis and in pathological contexts. Apoptosis is executed mainly through the intrinsic pathway or the death receptor pathway, i.e., extrinsic pathway. These processes are tightly controlled by positive and negative regulators that dictate pro- or anti-apoptotic death receptor signaling. One of these regulators is the Fas Apoptotic Inhibitory Molecule (FAIM). This death receptor antagonist has two main isoforms, FAIM-S (short) which is the ubiquitously expressed, and a longer isoform, FAIM-L (long), which is mainly expressed in the nervous system. Despite its role as a death receptor antagonist, FAIM also participates in cell death-independent processes such as nerve growth factor-induced neuritogenesis or synaptic transmission. Moreover, FAIM isoforms have been implicated in blocking the formation of protein aggregates under stress conditions or de-regulated in certain pathologies such as Alzheimer’s and Parkinson’s diseases. Despite the role of FAIM in physiological and pathological processes, little is known about the molecular mechanisms involved in the regulation of its expression. Here, we seek to investigate the post-transcriptional regulation of FAIM isoforms by microRNAs (miRNAs). We found that miR-206, miR-1-3p, and miR-133b are direct regulators of FAIM expression. These findings provide new insights into the regulation of FAIM and may provide new opportunities for therapeutic intervention in diseases in which the expression of FAIM is altered.

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Faim knockout leads to gliosis and late‐onset neurodegeneration of photoreceptors in the mouse retina

Sirés

Turch-Anguera

Bogdanov

et al. 2021

J of Neuroscience Research

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Fas Apoptotic Inhibitory Molecule protein (FAIM) is a death receptor antagonist and an apoptosis regulator. It encodes two isoforms, namely FAIM-S (short) and FAIM-L (long), both with significant neuronal functions. FAIM-S, which is ubiquitously expressed, is involved in neurite outgrowth. In contrast, FAIM-L is expressed only in neurons and it protects them from cell death. Interestingly, FAIM-L is downregulated in patients and mouse models of Alzheimer's disease before the onset of neurodegeneration, and Faim transcript levels are decreased in mouse models of retinal degeneration. However, few studies have addressed the role of FAIM in the central nervous system, yet alone the retina. The retina is a highly specialized tissue, and its degeneration has proved to precede pathological mechanisms of neurodegenerative diseases. Here we describe that Faim depletion in mice damages the retina persistently and leads to late-onset photoreceptor death in older mice. Immunohistochemical analyses showed that Faim knockout (Faim −/− ) mice present ubiquitinated aggregates throughout the retina from early ages. Moreover, retinal cells released stress signals that can signal to Müller cells, as shown by immunofluorescence and qRT-PCR.Müller cells monitor retinal homeostasis and trigger a gliotic response in Faim −/− mice that becomes pathogenic when sustained. In this regard, we observed pronounced vascular leakage at later ages, which may be caused by persistent inflammation.These results suggest that FAIM is an important player in the maintenance of retinal homeostasis, and they support the premise that FAIM is a plausible early marker for late photoreceptor and neuronal degeneration.

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FAIM Is a Non-redundant Defender of Cellular Viability in the Face of Heat and Oxidative Stress and Interferes With Accumulation of Stress-Induced Protein Aggregates

Cited by 15 publications

References 40 publications

Fas Apoptosis Inhibitory Molecule Blocks and Dissolves Pathological Amyloid-β Species

Fas Apoptosis Inhibitory Molecule Blocks and Dissolves Pathological Amyloid-β Species

FAIM Is Regulated by MiR-206, MiR-1-3p and MiR-133b

Faim knockout leads to gliosis and late‐onset neurodegeneration of photoreceptors in the mouse retina

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