Pathological Modification of TDP-43 in Amyotrophic Lateral Sclerosis with SOD1 Mutations

Jeon, Gun Sang; Shim, Yumi; Lee, Doyeon; Kim, Jun Soon; Kang, Mi Ae; Ahn, So Hyun; Shin, Je Young; Geum, Dongho; Hong, Yoon Ho; Sung, Jung Joon

doi:10.1007/s12035-018-1218-2

Cited by 53 publications

(54 citation statements)

References 55 publications

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“…Remarkably, in the autopsy materials from the patients with ALS, strong IL-10 immunoreactivity colocalizes with inclusions containing TAR DNA-binding protein (TDP)-43 in motor neurons, supporting the concept that IL-10 is involved in the pathogenesis of ALS. [25][26][27] Specifically, for patients with C9orf72HRE ALS, we observed an association between plasma IL-1β and survival, indicating the involvement of IL-1β in this subset of patients, but not in mSOD1 ALS or OALS. This finding may add to an explanation for the poor prognosis among patients with C9orf72HRE ALS.…”

Section: Immunopathologic Processes Related To Als Genetic Variantsmentioning

confidence: 63%

Inflammatory profiles relate to survival in subtypes of amyotrophic lateral sclerosis

Olesen

Wuolikainen

Nilsson

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo investigate inflammatory cytokines in patients with motor neuron disease (MND) evaluating the putative contribution of amyotrophic lateral sclerosis (ALS)-causing gene variants. MethodsThis study is a retrospective case series with prospective follow-up (1994-2016) of 248 patients with MND, of whom 164 had ALS who were screened for mutations in the genes for SOD1 and C9orf72. Paired CSF and plasma were collected at the diagnostic evaluation before treatment. A panel of cytokines were measured blindly via digital ELISA on the Simoa platform. ResultsTime from disease onset to death was longer for patients with ALS-causing SOD1 mutations (mSOD1, n = 24) than those with C9orf72 hexanucleotide repeat expansion (C9orf72HRE) ALS (n = 19; q = 0.001) and other ALS (OALS) (n = 119; q = 0.0008). Patients with OALS had higher CSF tumor necrosis factor alpha (TNF-α) compared with those with C9orf72HRE ALS (q = 0.014). Patients with C9orf72HRE ALS had higher CSF interferon alpha compared with those with OALS and mSOD1 ALS (q = 0.042 and q = 0.042). In patients with ALS, the survival was negatively correlated with plasma interleukin (IL) 10 (hazard ratio [HR] 1.17, 95% CI 1.05-1.30). Plasma TNF-α, IL-10, and TNF-related apoptosis-inducing ligand (TRAIL) (HR 1.01 [1.00-1.02], 1.15 [1.02-1.30], and 1.01 [1.00-1.01], respectively) of patients with OALS, plasma IL-1β .5]) of patients with C9orf72HRE ALS, and CSF TRAIL (10.5 [1.12-98.6]) of patients with mSOD1 ALS all correlated negatively with survival. ConclusionsDifferences in survival times in ALS subtypes were correlated with cytokine levels, suggesting specific immune responses related to ALS genetic variants. Glossary ALS = amyotrophic lateral sclerosis; dsRNA = double-stranded RNA; FTD = frontotemporal dementia; HR = hazard ratio; HRE = hexanucleotide repeat expansion; IFN = interferon; IFN-α = interferon alpha; IL = interleukin; IVIg = IV immunoglobulin; MND = motor neuron disease; OALS = other amyotrophic lateral sclerosis; OMND = other motor neuron diseases; PBP = progressive bulbar palsy; TNF = tumor necrosis factor; TNF-α = tumor necrosis factor alpha; TRAIL = TNFrelated apoptosis-inducing ligand.

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Section: Immunopathologic Processes Related To Als Genetic Variantsmentioning

confidence: 63%

Inflammatory profiles relate to survival in subtypes of amyotrophic lateral sclerosis

Olesen

Wuolikainen

Nilsson

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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“…In ALS, truncated forms of TDP-43 are found in ALS aggregates, more predominantly in the cortex but also to a lesser extent in the spinal cord [55][56][57][58][59]. The Nterminally truncated, C-terminal fragments 35 kDa (CTF35) and 25 kDa (CTF25) are the most notable "species" of TDP-43 [8,[60][61][62]. Several species of TDP-43 exist and are produced through translation of alternatively spliced isoforms or through proteolytic cleavage at the post-translational level (Fig.…”

Section: Main Textmentioning

confidence: 99%

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Suk

Rousseaux

2020

Mol Neurodegeneration

208

170

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Since its discovery as a primary component in cytoplasmic aggregates in post-mortem tissue of patients with Amyotrophic Lateral Sclerosis (ALS), TAR DNA Binding Protein 43 kDa (TDP-43) has remained a central focus to understand the disease. TDP-43 links both familial and sporadic forms of ALS as mutations are causative for disease and cytoplasmic aggregates are a hallmark of nearly all cases, regardless of TDP-43 mutational status. Research has focused on the formation and consequences of cytosolic protein aggregates as drivers of ALS pathology through both gainand loss-of-function mechanisms. Not only does aggregation sequester the normal function of TDP-43, but these aggregates also actively block normal cellular processes inevitably leading to cellular demise in a short time span. Although there may be some benefit to therapeutically targeting TDP-43 aggregation, this step may be too late in disease development to have substantial therapeutic benefit. However, TDP-43 pathology appears to be tightly linked with its mislocalization from the nucleus to the cytoplasm, making it difficult to decouple the consequences of nuclearto-cytoplasmic mislocalization from protein aggregation. Studies focusing on the effects of TDP-43 mislocalization have demonstrated both gain-and loss-of-function consequences including altered splicing regulation, over responsiveness to cellular stressors, increases in DNA damage, and transcriptome-wide changes. Additionally, mutations in TARDBP confer a baseline increase in cytoplasmic TDP-43 thus suggesting that small changes in the subcellular localization of TDP-43 could in fact drive early pathology. In this review, we bring forth the theme of protein mislocalization as a key mechanism underlying ALS, by highlighting the importance of maintaining subcellular proteostasis along with the gain-and loss-of-functional consequences when TDP-43 localization is dysregulated. Additional research, focusing on early events in TDP-43 pathogenesis (i.e. to the protein mislocalization stage) will provide insight into disease mechanisms, therapeutic targets, and novel biomarkers for ALS.

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“…This is of great importance, as SOD1 mutations do not result in TDP-43 inclusions in the SOD1 G93A model, with this hallmark of disease pathogenesis being not commonly present in either SOD1 patients or mice (Stephenson and Amor, 2017). However, other SOD1 models such as SOD1 G86S do exhibit TDP-43 inclusions and could be used to overcome this pitfall (Jeon et al, 2019). Furthermore, while patients develop the disease with basal quantities of the mutated protein, mice show very high overexpression of the mutated SOD1 protein (Lutz, 2018).…”

Section: Sod1 Modelsmentioning

confidence: 99%

P2X7 Receptor Antagonism as a Potential Therapy in Amyotrophic Lateral Sclerosis

Ruiz-Ruiz

Calzaferri

Garcı́a

2020

Front. Mol. Neurosci.

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This review focuses on the purinergic ionotropic receptor P2X7 (P2X7R) as a potential target for developing drugs that delay the onset and/or disease progression in patients with amyotrophic lateral sclerosis (ALS). Description of clinical and genetic ALS features is followed by an analysis of advantages and drawbacks of transgenic mouse models of disease based on mutations in a bunch of proteins, particularly Cu/Zn superoxide dismutase (SOD1), TAR-DNA binding protein-43 (TDP-43), Fused in Sarcoma/Translocated in Sarcoma (FUS), and Chromosome 9 open reading frame 72 (C9orf72). Though of limited value, these models are however critical to study the proof of concept of new compounds, before reaching clinical trials. The authors also provide a description of ALS pathogenesis including protein aggregation, calcium-dependent excitotoxicity, dysfunction of calcium-binding proteins, ultrastructural mitochondrial alterations, disruption of mitochondrial calcium handling, and overproduction of reactive oxygen species (ROS). Understanding disease pathogenic pathways may ease the identification of new drug targets. Subsequently, neuroinflammation linked with P2X7Rs in ALS pathogenesis is described in order to understand the rationale of placing the use of P2X7R antagonists as a new therapeutic pharmacological approach to ALS. This is the basis for the hypothesis that a P2X7R blocker could mitigate the neuroinflammatory state, indirectly leading to neuroprotection and higher motoneuron survival in ALS patients.

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Pathological Modification of TDP-43 in Amyotrophic Lateral Sclerosis with SOD1 Mutations

Cited by 53 publications

References 55 publications

Inflammatory profiles relate to survival in subtypes of amyotrophic lateral sclerosis

Inflammatory profiles relate to survival in subtypes of amyotrophic lateral sclerosis

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

P2X7 Receptor Antagonism as a Potential Therapy in Amyotrophic Lateral Sclerosis

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