Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neuron-like cells. Mutations in the RNA- and DNA-binding proteins, fused in sarcoma (FUS) and transactive response DNA-binding protein 43 kDa (TDP-43), are responsible for 5–10% of familial and 1% of sporadic ALS cases. Importantly, aggregation of misfolded FUS or TDP-43 is also characteristic of several neurodegenerative disorders in addition to ALS, including frontotemporal lobar degeneration. Moreover, splicing deregulation of FUS and TDP-43 target genes as well as mitochondrial abnormalities are associated with disease-causing FUS and TDP-43 mutants. While progress has been made to understand the functions of these proteins, the exact mechanisms by which FUS and TDP-43 cause ALS remain unknown. Recently, we discovered that, in addition to being up-regulated in spinal cords of ALS patients, the novel protein oxidative resistance 1 (Oxr1) protects neurons from oxidative stress-induced apoptosis. To further understand the function of Oxr1, we present here the first interaction study of the protein. We show that Oxr1 binds to Fus and Tdp-43 and that certain ALS-associated mutations in Fus and Tdp-43 affect their Oxr1-binding properties. We further demonstrate that increasing Oxr1 levels in cells expressing specific Fus and Tdp-43 mutants improves the three main cellular features associated with ALS: cytoplasmic mis-localization and aggregation, splicing changes of a mitochondrial gene and mitochondrial defects. Taken together, these findings suggest that OXR1 may have therapeutic benefits for the treatment of ALS and related neurodegenerative disorders with TDP-43 pathology.

Differential toxicity of TAR DNA‐binding protein 43 isoforms depends on their submitochondrial localization in neuronal cells

“…This hypothesis is supported by the recent observation that ALS‐related TDP‐43 mutations are responsible for the alteration of the splicing pattern of nuclear‐transcribed mRNAs coding for mitochondrial fission regulator‐1, an IMM protein involved in mitochondrial fission (Finelli et al . ). A third possibility is that damage is induced directly (through sequestration or other unknown mechanisms) by the small fraction of the protein that localizes into these organelles.…”

Autophagy Dysregulation in ALS: When Protein Aggregates Get Out of Hand

“…In addition, Keap1 immunoreactivity has been detected in the skein-like inclusions from the spinal cords of ALS patients, possibly through an interaction with p62/SQSTM1, a protein that has been observed in several ALS inclusions (Goode et al, 2016 ). Another mechanism of oxidative stress-induced autophagy in ALS is through stress granule formation and subsequent degradation of stress granules by autophagy (Finelli et al, 2015 ). In fact, when the oxidative stress resistance protein (Oxr1) was upregulated in neuronal cells, FUS and TDP-43’s cytoplasmic mislocalization and aggregation was significantly reduced (Finelli et al, 2015 ).…”

“…Another mechanism of oxidative stress-induced autophagy in ALS is through stress granule formation and subsequent degradation of stress granules by autophagy (Finelli et al, 2015 ). In fact, when the oxidative stress resistance protein (Oxr1) was upregulated in neuronal cells, FUS and TDP-43’s cytoplasmic mislocalization and aggregation was significantly reduced (Finelli et al, 2015 ). This suggests an important pathogenic role of oxidative stress in stress granule formation in FUS - and TDP-43 - associated ALS.…”

Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity

“…Over the last decade, TDP-43, FUS, Matrin-3, VCP and several other RNA-binding proteins have been found to be linked with causing ALS pathogenesis suggesting that disease-causing mutations perturbing RNA metabolism might be central to causing ALS pathogenesis [26, 51, 52, 64, 68]. This is supported by recent studies showing that ALS-causing mutations in RNA binding proteins cause defects in RNA splicing, stability, transcription, mRNA processing, translation and transport, which may lead to gross functional impairments in several key biological pathways [3, 5–7, 10, 18–23, 25, 30, 31, 33, 34, 60, 61, 63, 65, 66]. …”