FAIM Opposes Aggregation of Mutant SOD1 That Typifies Some Forms of Familial Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative illness that is unremittingly fatal and for which no effective treatment exists. All forms of ALS are characterized by protein aggregation. In familial forms of ALS, specific and heritable aggregation-prone proteins have been identified, such as mutant superoxide dismutase (SOD1). It has been suggested that a factor capable of preventing mutant SOD1 protein aggregation and/or disassembling mutant SOD1 protein aggregates would ameliorate SOD1-associated forms of familial ALS. Here we identify Fas Apoptosis Inhibitory Molecule (FAIM), a highly evolutionarily conserved 20 kDa protein, as an agent with this activity. We show FAIM counteracts intracellular accumulation of mutant SOD1 protein aggregates, which is increased in the absence of FAIM, as determined by pulseshape analysis and filter trap assays. In a cell-free system, FAIM inhibits aggregation of mutant SOD1, and further disassembles and solubilizes established mutant SOD1 protein aggregates, as determined by thioflavin T (ThT), filter trap, and sedimentation assays. In sum, we report here a previously unknown activity of FAIM that opposes ALS disease-related protein aggregation and promotes proteostasis of an aggregation-prone ALS protein.

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

“…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.…”

“…His-tag protein expression vectors were constructed using pTrcHis TA vector (Themo Fisher Science, #K441001) according to the manufacturer’s instructions as previously described ( Kaku et al, 2020 ). In brief, PCR amplified target genes were TA-cloned into the pTrcHis TA vector (Themo Fisher Science) and inserted DNA was verified by sequencing (Genewiz).…”

“…The physiological role of FAIM has been enigmatic for many years because of the absence of any homologous protein sequences, or any recognizable consensus effector/binding motifs; with limited structural information on the full peptide it has been difficult to predict FAIM’s authentic functions. Recent work showed that FAIM opposes aggregation of a mutant protein associated with some hereditary forms of ALS, suggesting a role in proteostasis ( Kaku et al, 2020 ). However, it is unclear whether this activity extends to other aggregation-prone proteins and/or other disease states; in particular, whether and to what extent FAIM can antagonize pathogenic Aβ species remains unexplored.…”

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

“…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.…”

FAIM-L - SIVA-1: Two Modulators of XIAP in Non-Apoptotic Caspase Function

“…Recently, a relationship between FAIM and protein aggregation became evident ( Kaku et al, 2020 ) pointing to a function of FAIM in protein homeostasis. FAIM is able to protect against environmental insults that cause accumulation of cytotoxic and aggregated proteins, such as oxidative stress, which are frequently found in the main neurodegenerative diseases.…”