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

Abstract

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.

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

“…The obese phenotype described by Lam’s group was not reproduced in a second Faim -KO mice generated by Dr. Rothstein’s group ( Kaku and Rothstein, 2020 ), and in our study with the former model some phenotypic characteristics changed based on the genetic background of the mice strain used. However, our group recently identified a retinal neurodegenerative phenotype in Dr. Huo’s model, compatible with the observations on protein homeostasis reported by Dr. Rothstein ( Sirés et al, 2021 ). Several factors can influence the appearance of phenotypes when analyzing mice models, such as genetic background of mice strain, flanking genes modifications during the generation of the mice, KO generation methodology, or environmental factors.…”

“…Therefore, FAIM-L decrease in AD could also be pathologically linked to a more rapid, aggressive Aβ aggregation. In a Faim-KO mice model ( Huo et al, 2016 ), we identified the presence of ubiquitinated aggregates throughout the retina, a gliotic activation response in the Müller cells, and pronounced vascular leakage that lead to late-onset photoreceptor cell death ( Sirés et al, 2021 ).…”

FAIM Enhances the Efficacy of Mesenchymal Stem Cell Transplantation by Inhibiting JNK-Induced c-FLIP Ubiquitination and Degradation

“…However, to date, the effects of FAIM on c-FLIP expression are not fully understood. FAIM has been reported to exert its biological effects by reducing ubiquitination; FAIM was found to reduce the ubiquitination and degradation of XIAP via direct interaction [ 48 ], FAIM knockout led to the presentation of ubiquitinated aggregates in the retina [ 49 ], and FAIM protects glutaminase C from ubiquitination and induces cancer cell proliferation in lung adenocarcinoma [ 14 ]. Here, we found that FAIM could maintain c-FLIP stabilization under hypoxic conditions by protecting c-FLIP from ubiquitination and degradation, thus protecting MSCs from apoptosis.…”