Disruption of ER−mitochondria signalling in fronto-temporal dementia and related amyotrophic lateral sclerosis

Lau, Dawn H. W.; Hartopp, Naomi; Welsh, Natalie J.; Mueller, Sarah B.; Glennon, Elizabeth; Mórotz, Gábor M.; Annibali, Ambra; Gómez‐Suaga, Patricia; Stoica, Radu; Paillusson, Sébastien; Miller, Christopher C.J.

doi:10.1038/s41419-017-0022-7

Cited by 56 publications

(50 citation statements)

References 116 publications

(136 reference statements)

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“…Case 4: The protein TDP-43 55 binds to chromosomally integrated trans-activation response element (TAR) DNA and represses HIV-1 transcription 56 . In addition, it is implicated in amyotrophic lateral sclerosis (ALS) and neurodegenerative diseases 57,58 . ODiNPred correctly identifies the folded domains of the N-terminus and the two RNA recognition motifs, having both large experimental and predicted Z-scores ( Fig.…”

Section: Evaluation Of Odinpred On Four Important Examples Of Disordementioning

confidence: 99%

ODiNPred: comprehensive prediction of protein order and disorder

Dass

Mulder

Nielsen

2020

Sci Rep

162

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Structural disorder is widespread in eukaryotic proteins and is vital for their function in diverse biological processes. It is therefore highly desirable to be able to predict the degree of order and disorder from amino acid sequence. It is, however, notoriously difficult to predict the degree of local flexibility within structured domains and the presence and nuances of localized rigidity within intrinsically disordered regions. To identify such instances, we used the CheZOD database, which encompasses accurate, balanced, and continuous-valued quantification of protein (dis)order at amino acid resolution based on NMR chemical shifts. To computationally forecast the spectrum of protein disorder in the most comprehensive manner possible, we constructed the sequence-based protein order/disorder predictor ODiNPred, trained on an expanded version of CheZOD. ODiNPred applies a deep neural network comprising 157 unique sequence features to 1325 protein sequences together with the experimental NMR chemical shift data. Cross-validation for 117 protein sequences shows that ODiNPred better predicts the continuous variation in order along the protein sequence, suggesting that contemporary predictors are limited by the quality of training data. The inclusion of evolutionary features reduces the performance gap between ODiNPred and its peers, but analysis shows that it retains greater accuracy for the more challenging prediction of intermediate disorder.

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Section: Evaluation Of Odinpred On Four Important Examples Of Disordementioning

confidence: 99%

ODiNPred: comprehensive prediction of protein order and disorder

Dass

Mulder

Nielsen

2020

Sci Rep

162

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“…Once the normal working of these basic processes is disrupted, this is then reflected in the viability/efficiency of other pathways such as nucleo‐cytoplasmic transport of mRNAs and proteins , protein translation or stress granule dynamics . Eventually, the damage spreads to various cellular organelles such as the Endoplasmic Reticulum (ER) and mitochondria and this eventually leads to the premature death of the affected neurons as schematically summarized in Figure .…”

Section: General Overview Of Ftld Pathological Mechanismsmentioning

confidence: 99%

Review: Molecular pathology of frontotemporal lobar degenerations

Borroni

Alberici

Buratti

2019

Neuropathology Appl Neurobio

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Frontotemporal lobar degeneration (FTLD) is a group of disorders that principally affect the frontal and temporal lobes of the brain. In many parts of the world, FTLD is rapidly becoming a serious health burden on society and, as a result, the molecular mechanisms that underlie its onset and development have been the target of intense research efforts in recent years. Nonetheless, despite crucial pathological and genetic discoveries in this area much is still uncertain about how the many genes associated with this disease cause the observed neurodegeneration. Moreover, it has not been easy to define the molecular mechanisms that account for the clinical and pathological heterogeneity of the various FTLD subtypes, characterized by aggregates of Tau, TAR‐DNA‐Binding Protein‐43 (TDP‐43), and less often Fused in Sarcoma (FUS) protein. In this review, we will examine some of the emerging discoveries in this field: from the recent importance of autoimmunity to the presence of substantial variations in the composition and localization of TDP‐43 and FUS brain aggregates in patients, and how they might affect the course of the disease. All together, these new results demonstrate how the observed clinical heterogeneity underlies considerable complexity at both the molecular and the disease pathway level. A better characterization of all this complexity will be essential for a more accurate stratification of patient cohorts for further studies and, eventually, for trials of therapy.

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“…However, the localization and enrichment of some proteins in MAM structures remains under debate. Several elegant reviews provide detailed information on how MAM disturbances are involved in human diseases [56][57][58][59][60][61][62][63][64][65][66][67][68][69][70].…”

Section: Inflammasome Formationmentioning

confidence: 99%

Mitochondria-associated endoplasmic reticulum membranes in the heart

Zou

2019

Archives of Biochemistry and Biophysics

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reviews on other MAM proteins and functions [7-9] exist for readers to acquire more information on other topics. 2. Functions of MAMs ER-mitochondria contact sites have received much attention due to their key regulation of several fundamental cellular processes (Table 1), including lipid and calcium (Ca 2+) homeostasis, initiation of autophagy and mitochondrial division, and metabolic shifts. 2.1. Ca 2+ transfer Ca 2+ is required by mitochondria to generate adenosine triphosphate (ATP) via the tricarboxylic acid cycle, as several mitochondrial enzymes involved in ATP synthesis are regulated by Ca 2+ [7, 10, 11]. However, excessive uptake of Ca 2+ by mitochondria leads to cell apoptosis via the opening of mitochondrial permeability transition pores (MPTPs) [7]. Ca 2+ transfer from ER to mitochondria is a well-characterized function of ER-mitochondria tethering. Localized Ca 2+ spikes released from ER via inositol 1,4,5-trisphosphate receptor (IP 3 R) channels stimulate mitochondrial Ca 2+ uptake. Ca 2+ passes through voltagedependent anion channel 1 (VDAC1) on outer mitochondrial membranes and mitochondrial Ca 2+ uniporters on inner mitochondrial membranes [12, 13]. A 75-kDa glucose-regulated protein (GRP75) is required for coupling VDAC1 to IP 3 Rs to form VDAC1/GRP75/IP 3 R channel complexes [14]. As overexpression of GRP75 does not increase ER-mitochondria contact, it is likely that GRP75 functions at established contacts to regulate mitochondrial Ca 2+ uptake [14]. Recent studies identify numerous regulators of IP 3 R channels at ER-mitochondria contacts. Promyelocytic leukemia protein (PML) was recently found in MAM fractions in a complex with protein kinase B (PKB/AKT) and protein phosphatase 2A (PP2A) [15]. Active, phosphorylated AKT phosphorylates IP 3 R and inhibits IP 3 R Ca 2+ release, protecting mitochondria from mounting a Ca 2+-mediated apoptotic response, whereas PP2A phosphatase activity deactivates AKT through dephosphorylation [16, 17]. PML may recruit PP2A, which inactivates AKT and facilitates IP 3 R-mediated Ca 2+ release in response to apoptotic stimuli. Ablation or silencing of mitofusin 2 (MFN2) in mouse embryonic fibroblasts (MEFs) and HeLa cells inhibits ER-mitochondria interactions, which suppresses mitochondrial Ca 2+ uptake in [9] response to stimuli that generate IP 3 [18]. A mammalian ortholog of yeast Mmm1, SMP domain-containing protein (PDZD8), is also present at ERmitochondria contact sites [19]. PDZD8 is required for the formation of ER-mitochondria contacts and ER-mitochondria Ca 2+ transfer in mammalian cells [19]. MAMs are generally considered as signaling platforms from which several modulators regulate VDAC1/GRP75/IP 3 R channel activity under physiological and pathological conditions [9]. Future work is needed to uncover regulatory proteins in the Ca 2+ microdomain and to clarify the mechanisms by which Ca 2+ is transferred from the ER into mitochondria.

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Disruption of ER−mitochondria signalling in fronto-temporal dementia and related amyotrophic lateral sclerosis

Cited by 56 publications

References 116 publications

ODiNPred: comprehensive prediction of protein order and disorder

ODiNPred: comprehensive prediction of protein order and disorder

Review: Molecular pathology of frontotemporal lobar degenerations

Mitochondria-associated endoplasmic reticulum membranes in the heart

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