The RNA-binding motif 45 (RBM45) protein accumulates in inclusion bodies in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) patients

Collins, Mahlon A; Riascos, David; Kovalik, Tina; An, Jiyan; Krupa, Kelly; Krupa, Kristin; Hood, Brian L.; Conrads, Thomas P.; Renton, Alan E.; Traynor, Bryan J.; Bowser, Robert

doi:10.1007/s00401-012-1045-x

Cited by 72 publications

(95 citation statements)

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“…No significant changes in total RBM45 levels ( Fig. 1D) were observed, consistent with our previously reported findings (9). Given that oxidative stress is a wellreported pathogenic factor in ALS, these results support that RBM45 subcellular distribution is regulated by oxidative stress both in vitro and in vivo.…”

Section: Rbm45 Is Regulated By Oxidative Stress In Vitro and In Als Ssupporting

confidence: 92%

“…ALS and nonneurologic disease control postmortem tissue samples were obtained from the University of Pittsburgh ALS Tis- Table 2, as is the presence or absence of RBM45 inclusions in motor neurons, as determined in our previous study (9). Statistical analysis was performed by using the Student t test.…”

Section: Methodsmentioning

confidence: 99%

“…We previously demonstrated that RBM45 was contained in cytoplasmic inclusions of neurons within the brain and spinal cord of ALS patients (9). Although the levels of RBM45 were increased in the CSF of ALS patients, little is known about its function.…”

Section: Rbm45 Is Regulated By Oxidative Stress In Vitro and In Als Smentioning

confidence: 99%

“…Recently, we linked another RNA binding protein, RBM45, to ALS using a proteomic screen of cerebrospinal fluid (CSF) from ALS and control subjects (9). RBM45, also known as Drb1, was first identified as a novel RNA binding protein that functions in neural development (10).…”

mentioning

confidence: 99%

“…By using a large liquid chromatography-tandem mass spectrometry (LC-MS/MS) unbiased proteomic analysis of CSF from 250 subjects, RBM45 levels were found to be increased in the CSF of ALS patients (9). ALS spinal cord motor neurons exhibited RBM45-positive cytoplasmic inclusions bearing a striking resemblance to those seen with TDP-43 and FUS in ALS motor neurons, and colocalization between TDP-43 and RBM45 in cytoplasmic inclusions was observed (9). Extensive RBM45 pathology was observed in patients with C9ORF72 repeat expansions.…”

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confidence: 99%

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RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

Bakkar

Kousari

Kovalik

et al. 2015

Molecular and Cellular Biology

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons. Various factors contribute to the disease, including RNA binding protein dysregulation and oxidative stress, but their exact role in pathogenic mechanisms remains unclear. We have recently linked another RNA binding protein, RBM45, to ALS via increased levels of protein in the cerebrospinal fluid of ALS patients and its localization to cytoplasmic inclusions in ALS motor neurons. Here we show RBM45 nuclear exit in ALS spinal cord motor neurons compared to controls, a phenotype recapitulated in vitro in motor neurons treated with oxidative stressors. We find that RBM45 binds and stabilizes KEAP1, the inhibitor of the antioxidant response transcription factor NRF2. ALS lumbar spinal cord lysates similarly show increased cytoplasmic binding of KEAP1 and RBM45. Binding of RBM45 to KEAP1 impedes the protective antioxidant response, thus contributing to oxidative stress-induced cellular toxicity. Our findings thus describe a novel link between a mislocalized RNA binding protein implicated in ALS (RBM45) and dysregulation of the neuroprotective antioxidant response seen in the disease.A myotrophic lateral sclerosis (ALS) is a fatal idiopathic adultonset neurodegenerative disease characterized by a loss of motor neurons in the brain, brain stem, and spinal cord, with consequent atrophy of associated muscles (1, 2). Incidence rates are 1 to 3 cases per 100,000 individuals per year. Pathogenic mechanisms underlying the disease are not fully understood. Approximately 5 to 10% of all ALS cases are familial (3), with the remaining cases being termed sporadic, contributing to the clinical heterogeneity within the patient population. Nevertheless, typical hallmarks of ALS include neuronal atrophy, mitochondrial dysfunction, excitotoxicity, oxidative stress, and ubiquitinated cellular inclusions (4, 5). A growing number of genes with diverse functions have been implicated in the disease etiology. Mutations in a number of RNA binding proteins have been linked to ALS, including TAR DNA binding protein 43 (TDP-43) and Fused in Sarcoma (FUS) (6). Mutations in these genes result in reduced levels in the nucleus and their accumulation in cytoplasmic ubiquitin-positive inclusions (7). Both TDP-43 and FUS possess prion-like domains and relocate to cytoplasmic stress granules under stress conditions, suggesting potential pathology commonalities (8). Genetic alterations in these and other RNA binding proteins link RNA metabolism to the pathobiology of ALS.Recently, we linked another RNA binding protein, RBM45, to ALS using a proteomic screen of cerebrospinal fluid (CSF) from ALS and control subjects (9). RBM45, also known as Drb1, was first identified as a novel RNA binding protein that functions in neural development (10). RBM45 possesses three RNA recognition motifs (RRMs) as well as a C-terminal nuclear localization sequence (10). By using a large liquid chromatography-tandem mass spectrometry (LC-MS/MS) unbia...

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Section: Rbm45 Is Regulated By Oxidative Stress In Vitro and In Als Ssupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Rbm45 Is Regulated By Oxidative Stress In Vitro and In Als Smentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

Bakkar

Kousari

Kovalik

et al. 2015

Molecular and Cellular Biology

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Gamma‐synuclein pathology in amyotrophic lateral sclerosis

Peters

Shelkovnikova

Highley

et al. 2014

Ann Clin Transl Neurol

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ObjectiveThe prominent histopathological feature of the amyotrophic lateral sclerosis (ALS) is the presence of intracellular inclusions in degenerating neurons and their axons. The appearance and localization of these pathological structures depend on an aggregated protein that forms their scaffold. We investigated if γ-synuclein, an aggregation-prone protein highly expressed in healthy motor neurons, and predominantly localized in their axons and synaptic terminals is involved in ALS pathology.MethodsImmunostaining of histological sections and sequential protein extraction from postmortem neural samples followed by immunoblotting.ResultsImmunohistochemical screening revealed a subset of sporadic (9 of 31) and familial (8 of 23) ALS cases with a novel type of pathology characterized by the accumulation of γ-synuclein in distinct profiles within the dorsolateral column. Sequential fractionation of proteins from the spinal cord tissues revealed detergent-insoluble γ-synuclein species specifically in the dorsolateral corticospinal tracts of a ALS patient with γ-synuclein-positive profiles in this region. These profiles are negative for protein markers commonly found in pathological inclusions in the spinal cord of ALS patients and most probably represent degenerated axons of upper motor neurons that have lost their neurofilaments. A subset of these profiles was found in association with phagocytic cells positive for Mac-2/Galectin-3. A smaller subset of studied ALS cases (4 of 54) contained large cytoplasmic inclusions in the cell body of remaining spinal motor neurons.InterpretationOur observations suggest that pathological aggregation of γ-synuclein might contribute to the pathogenesis of ALS.

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Oligodendrocyte pathology exceeds axonal pathology in white matter in human amyotrophic lateral sclerosis

Pons

Higginbottom

Cooper‐Knock

et al. 2020

The Journal of Pathology

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. The majority of cases are sporadic (sALS), while the most common inherited form is due to C9orf72 mutation (C9ALS). A high burden of inclusion pathology is seen in glia (including oligodendrocytes) in ALS, especially in C9ALS. Myelin basic protein (MBP) messenger RNA (mRNA) must be transported to oligodendrocyte processes for myelination, a possible vulnerability for normal function. TDP43 is found in pathological inclusions in ALS and is a component of mRNA transport granules. Thus, TDP43 aggregation could lead to MBP loss. Additionally, the hexanucleotide expansion of mutant C9ALS binds hnRNPA2/B1, a protein essential for mRNA transport, causing potential further impairment of hnRNPA2/B1 function, and thus myelination. Using immunohistochemistry for p62 and TDP43 in human post‐mortem tissue, we found a high burden of glial inclusions in the prefrontal cortex, precentral gyrus, and spinal cord in ALS, which was greater in C9ALS than in sALS cases. Double staining demonstrated that the majority of these inclusions were in oligodendrocytes. Using immunoblotting, we demonstrated reduced MBP protein levels relative to PLP (a myelin component that relies on protein not mRNA transport) and neurofilament protein (an axonal marker) in the spinal cord. This MBP loss was disproportionate to the level of PLP and axonal loss, suggesting that impaired mRNA transport may be partly responsible. Finally, we show that in C9ALS cases, the level of oligodendroglial inclusions correlates inversely with levels of hnRNPA2/B1 and the number of oligodendrocyte precursor cells. We conclude that there is considerable oligodendrocyte pathology in ALS, which at least partially reflects impairment of mRNA transport. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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The RNA-binding motif 45 (RBM45) protein accumulates in inclusion bodies in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) patients

Cited by 72 publications

References 46 publications

RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

Gamma‐synuclein pathology in amyotrophic lateral sclerosis

Oligodendrocyte pathology exceeds axonal pathology in white matter in human amyotrophic lateral sclerosis

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