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| The RNA Binding proteins TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS) function in several aspects of RNA metabolism. (1) TDP-43 regulates the transcription of UG repeat containing genes by stabilizing the binding of cohesin and nipped B to DNA. FUS binds to RNA Pol II to regulate the transcription of target genes. (2) Both TDP-43 and FUS regulate the splicing of target genes; TDP-43 via its interaction with UG repeats and FUS via its interaction with components of the spliceosome. (3) In disease, defects in RNA processing at any stage lead to transport defects (nucleo/cytoplasmic, axonal). (4,5) TDP-43 and FUS also alter stress granule dynamics, which can in turn impact mRNA translation. Dipeptide repeat proteins (DPRs) from C9orf72 repeat expansions have also been shown to associate with stress granules. Synaptic dysfunction and failure likely result from defects in RNA processing. Proteins and RNA as indicated. C9orf72 collectively represents G 4 C 2 repeats and DPRs.
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Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. The molecular mechanisms underlying disease pathogenesis remain largely unknown. Multiple genetic loci including genes involved in proteostasis and ribostasis have been linked to ALS providing key insights into the...
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... How might otherwise distinct mutations converge to produce the same phenotypic outcome across FALS and SALS? Although several other RNA binding (e.g., senataxin, hnRNPA1 Chen et al., 2004;Kim et al., 2013) or stress granule associated proteins (e.g., TIA-1, profilin LiuYesucevitz et al., 2010;Wu et al., 2012;Figley et al., 2014) have been linked to ALS/FTD, here we will address some of these questions by reviewing recent literature on RNA metabolism in ALS and discuss how dysregulation of RNA processing steps may contribute to disease from the perspective of three critically important genes, namely TARDP, FUS and C9orf72 (Figure 1). ...
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... Both diseases are linked at the genetic, clinical and pathological levels, with each presenting as one end of a spectrum of overlapping clinical symptoms that are thought to represent a broad and continuous neurodegenerative disorder (Ling et al., 2013) . TDP-43, a ubiquitously expressed and predominantly nuclear RNA/DNA binding protein encoded by the TARDBP gene that is involved in multiple aspects of RNA processing through its RNA binding capacity (Coyne et al., 2017) (Buratti, 2021), is thought to play a central role in ALS and FTD pathogenesis as one of the main components of the proteinaceous inclusions that pathologically define the great majority of ALS and up to 50% of FTD cases (Neumann et al., 2006) . TDP-43 pathology, occurring when TDP-43 is depleted from the nucleus and sequestered as hyperphosphorylated insoluble aggregates in the cytoplasm, perikarya, and/or dystrophic neurites of affected neurons, is also present in all cases of the dementia entity limbic-predominant age-related TDP-43 encephalopathy (LATE) and up to 50% of Alzheimer's cases, that together with other disorders where TDP-43 pathology occurs, are collectively known as TDP-43 proteinopathies. ...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by the progressive degeneration of motor neurons in the cerebral cortex and spinal cord, with a rapid progression from diagnosis to death. The great majority of ALS cases and around 50% of FTD cases present with TDP-43 pathology, leading to mislocalization and cytoplasmic aggregation of TDP-43, which can result in both its loss of nuclear functions and a gain of toxicity in the cytoplasm. TDP-43 and other RNA-binding proteins accumulate in stress granules (SGs) under stress conditions. The ubiquitin-specific protease 10 (USP10) is an inhibitor of SGs assembly that has been recently linked to neurodegeneration. Here, we identified a new functional interaction between TDP-43 and USP10, in which USP10 can control multiple aspects of TDP-43 biology that are thought to play important roles in its involvement in disease pathogenesis, such as its cytoplasmic and nuclear aggregation, expression and splicing functionality. In turn, TDP-43 is also able to control diverse aspects of USP10 biology, such as its expression levels, aggregation and function. Critically, we found USP10 dysregulation in ALS and FTD patients, overall suggesting a possible role for USP10 in ALS/FTD pathogenesis.
... (TDP-43) and RNA-binding protein FUS (Fused in Sarcoma-FUS), are responsible for causing adverse effects to RNA metabolism as observed in ALS-afflicted motor neurons (MNs) (Yasuda et al. 2017;Kamelgarn et al. 2018;Suk and Rousseaux 2020;Asadi et al. 2021;Coyne et al. 2017), potentially leading to neuron death. Faulty protein metabolism in ALS-linked motor neurons leads to the formation of toxic cytoplasmic aggregates, which prevent proper transcription, RNA splicing/transport, and signaling at neuromuscular junctions (Theunissen et al. 2021). ...
... Faulty protein metabolism in ALS-linked motor neurons leads to the formation of toxic cytoplasmic aggregates, which prevent proper transcription, RNA splicing/transport, and signaling at neuromuscular junctions (Theunissen et al. 2021). Abnormal protein aggregation in ALS-afflicted motor neurons also depletes the presence of RNA-binding proteins in the nuclear lamina, further causing metabolic dysfunction (Coyne et al. 2017;Theunissen et al. 2021). This is due to the tendency for mutated RNA-binding proteins, specifically TDP-43 and FUS, to mislocalize in the cytoplasm instead of the nucleus (Coyne et al. 2017;Theunissen et al. 2021). ...
... Abnormal protein aggregation in ALS-afflicted motor neurons also depletes the presence of RNA-binding proteins in the nuclear lamina, further causing metabolic dysfunction (Coyne et al. 2017;Theunissen et al. 2021). This is due to the tendency for mutated RNA-binding proteins, specifically TDP-43 and FUS, to mislocalize in the cytoplasm instead of the nucleus (Coyne et al. 2017;Theunissen et al. 2021). ...
Amyotrophic lateral sclerosis (ALS) is a progressive, uncurable neurodegenerative disorder characterized by the degradation of motor neurons leading to muscle impairment, failure, and death. Senataxin, encoded by the SETX gene, is a human helicase protein whose mutations have been linked with ALS onset, particularly in its juvenile ALS4 form. Using senataxin’s yeast homolog Sen1 as a model for study, it is suggested that senataxin’s N-terminus interacts with RNA polymerase II, whilst its C-terminus engages in helicase activity. Senataxin is heavily involved in transcription regulation, termination, and R-loop resolution, enabled by recruitment and interactions with enzymes such as ubiquitin protein ligase SAN1 and ribonuclease H (RNase H). Senataxin also engages in DNA damage response (DDR), primarily interacting with the exosome subunit Rrp45. The Sen1 mutation E1597K, alongside the L389S and R2136H gain-of-function mutations to senataxin, is shown to cause negative structural and thus functional effects to the protein, thus contributing to a disruption in WT functions, motor neuron (MN) degeneration, and the manifestation of ALS clinical symptoms. This review corroborates and summarizes published papers concerning the structure and function of senataxin as well as the effects of their mutations in ALS pathology in order to compile current knowledge and provide a reference for future research. The findings compiled in this review are indicative of the experimental and therapeutic potential of senataxin and its mutations as a target in future ALS treatment/cure discovery, with some potential therapeutic routes also being discussed in the review.
... TDP-43 proteinopathies in ALS are characterized by (i) hyperphosphorylation, (ii) ubiquitination, (iii) protein aggregation, (iv) protein truncation forming prone-to-aggregation toxic C-terminal fragments of , and (v) nuclear depletion in neurons causing the nucleus to mislocalise to the cytoplasm. Collectively all of these disturbances reduce the level of functional and healthy J o u r n a l P r e -p r o o f TDP-43 in the cell nucleus which perturbs normal cellular function (a loss-of-function impact) and conversely, a high accumulation in cytoplasmic inclusions in the spinal cord and brain neurons which can have neurotoxic actions (a toxic gain-of-function impact, Fig.3) (Ayala et al., 2008;Coyne et al., 2017b;Ling et al., 2013;Neumann et al., 2006). ...
... The tardbp gene on chromosome 1 encodes a 414 amino acid-long TDP-43 protein that is mostly found in the nuclear region, although it also moves to the cytoplasmic region to perform certain functionalities (Ayala et al. 2008). TDP-43 plays varied roles pertaining to RNA metabolism; it is responsible for transporting and migrating the mRNA, miRNAs, and lncRNA (Coyne et al. 2017). TDP-43 acts together with many other proteins involved in diverse physiological activities, as shown by a global interactome analysis (Freibaum et al. 2010). ...
Neurodegeneration is a state of progressive decay of neuronal structure and function. It has gained scientific attention owing to the fact that available treatments for the neurodegenerative disorders only provide symptomatic relief, but do not cure them. As most of the neurodegenerative diseases are proteopathies, researchers have focused on studying the modulations in protein interaction networks that are responsible for the onset of these diseases. This chapter discusses the major neurodegenerative disorders at length, including their symptoms and pathophysiology. The chapter also furnishes information on the predicted as well as established protein interactions underlying the diseases.
... The major mechanisms of neurodegeneration in ALS proposed in the past decades include, but are not limited to, the following pathways: oxidative damage, 5 abnormal protein aggregation, [6][7][8] glutamate-induced excitotoxicity, 9,10 neuroinflammation, 11,12 mitochondrial dysfunction [13][14][15][16] , and RNA dysregulation [17][18][19] . Aberrant protein aggregation in motor neurons is an intracellular hallmark of ALS. ...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting from the progressive loss of both upper and lower motor neurons in the cerebral cortex, brainstem, and spinal cord. Currently, there are only two drugs, Riluzole (Rilutek) and Edaravone (Radicava), approved by FDA for ALS treatment. These two drugs are very expensive with only a few months of life extension. So far, there is no cure for ALS. Aberrant protein aggregation in motor neurons is an intracellular hallmark of ALS. The disturbance in protein homeostasis may contribute to the onset and progression of ALS. Autophagy plays an important role in degrading misfolded proteins and thereby preventing their aggregation. Pharmacological manipulation of autophagy has been proposed as a new therapeutic approach for treating ALS. IADB, a novel indole alkaloid derivative, has been reported to exert mitochondrial protection and cardioprotection through its autophagy-modulating potential. In our present study, we attempted to examine whether IADB has therapeutic potential in SOD1G93A-associated experimental models of ALS. We found that IADB could promote the clearance of SOD1G93A aggregates and reduce the overproduction of mitochondrial reactive oxygen species (ROS) in motor neuron-like NSC-34 cells transfected with SOD1G93A. We further examined the IADB in a mouse model of ALS. Administration of IADB started at the age of 55 days until the end stage of the disease. IADB treatment significantly increased LC3-II levels and decreased human SOD1 levels and p62 expression in the spinal cords of SOD1G93A mice, suggesting that IADB treatment could induce autophagy activation and promote clearance of mutant SOD1 aggregates in SOD1G93A mice. Moreover, IADB treatment could alleviate the activation of microglia and astrocytes and mitochondrial oxidative damage in the spinal cord of SOD1G93A mice. Finally, we demonstratedthat IADB treatment could improve motor performance and delay the onset and progression of the disease in a mouse model of ALS. The neuroprotective effects of IADB may mainly originate from its autophagy-promoting property.
... Numerous neurological illnesses, such as FTD, ALS, and LATE (limbic predominant age-dependent TDP-43 encephalopathy), are associated with the accumulation of TDP-43 ensembles in the central nervous system (CNS). TDP-43, like FUS, is found in SGs and has multiple functions related to RNA metabolism, such as processing of microRNA (miRNA) and long non-coding RNA (lncRNA) from primary transcript to mature form, stabilization and transport of mRNA, processing of RNA, precursor mRNA splicing, as well as transcription and translation [199,200]. The pathophysiology of TDP-43 assemblies in the cytoplasm is associated with the reduced TDP-43 protein levels in the nucleus [201]. ...
Recent evidence has shown that the processes of liquid-liquid phase separation (LLPS) or liquid-liquid phase transitions (LLPTs) are a crucial and prevalent phenomenon that underlies the biogenesis of numerous membrane-less organelles (MLOs) and biomolecular condensates within the cells. Findings show that processes associated with LLPS play an essential role in physiology and disease. In this review, we discuss the physical and biomolecular factors that contribute to the development of LLPS, the associated functions, as well as their consequences for cell physiology and neurological disorders. Additionally, the finding of mis-regulated proteins, which have long been linked to aggregates in neuropathology, are also known to induce LLPS/LLPTs, prompting a lot of interest in understanding the connection between aberrant phase separation and disorder conditions. Moreover, the methods used in recent and ongoing studies in this field are also explored, as is the possibility that these findings will encourage new lines of inquiry into the molecular causes of neurodegenerative diseases.
... TDP43 is also found mislocalized in 45% of patients with frontotemporal lobar degeneration (FTLD). TDP43 plays a critical role in several steps of mRNA metabolism by regulating transcription, mRNA transport and stabilization into the cytoplasm, translation and microRNA processing [6]. TDP43 dysregulation leads to many cellular abnormalities including abnormal accumulation of unfolded protein, excitotoxicity, nucleocytoplasmic transport defects, mitochondrial dysfunction and oxidative damage. ...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons. As a consequence, ALS patients display a locomotor disorder related to muscle weakness and progressive paralysis. Pathological mechanisms that participate in ALS involve deficient unfolded protein response, mitochondrial dysfunction and oxidative stress, among others. Finding a therapeutic target to break the vicious circle is particularly challenging. Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone that may be one of those targets. We here address and decipher the efficiency of S1R activation on a key ALS gene, TDP43, in zebrafish vertebrate model. While expression of mutant TDP43 (TDP43G348C) led to locomotor defects, treatment with the reference S1R agonist PRE-084 rescued motor performances in a zebrafish model. Treatment with the agonist ameliorated maximal mitochondrial respiration in the TDP43 context. We observed that TDP43G348C exacerbated ER stress induced by tunicamycin, resulting in increased levels of ER stress chaperone BiP and pro-apoptotic factor CHOP. Importantly, PRE-084 treatment in the same condition further heightened BiP levels but also EIF2α/ATF4 and NRF2 signalling cascades, both known to promote antioxidant protection during ER stress. Moreover, we showed that increasing NRF2 levels directly or by sulforaphane treatment rescued locomotor defects of TDP43G348C zebrafish. For the first time, we here provide the proof of concept that PRE-084 prevents mutant TDP43 toxicity by boosting ER stress response and antioxidant cascade through NRF2 signalling.
... This has been suggested in ALS models and post-mortem human material [57][58][59]. Alternative splicing of many RNA targets is altered in ALS [60] and key splicing factors and RNA binding proteins are known to function in or near synapses [61,62]. We find the spliceosome enriched within BA4 ALS synapses, and it would be important to unravel what effect this may have on the splicing and subsequent composition of synaptic proteins, especially given recent data linking TDP-43 mislocalisation to aberrant splicing and decreased expression of the synaptic protein Munc13-1 (UNC13A) [63,64]. ...
Increasing evidence suggests synaptic dysfunction is a central and possibly triggering factor in Amyotrophic Lateral Sclerosis (ALS). Despite this, we still know very little about the molecular profile of an ALS synapse. To address this gap, we designed a synaptic proteomics experiment to perform an unbiased assessment of the synaptic proteome in the ALS brain. We isolated synaptoneurosomes from fresh-frozen post-mortem human cortex (11 controls and 18 ALS) and stratified the ALS group based on cognitive profile (Edinburgh Cognitive and Behavioural ALS Screen (ECAS score)) and presence of a C9ORF72 hexanucleotide repeat expansion (C9ORF72-RE). This allowed us to assess regional differences and the impact of phenotype and genotype on the synaptic proteome, using Tandem Mass Tagging-based proteomics. We identified over 6000 proteins in our synaptoneurosomes and using robust bioinformatics analysis we validated the strong enrichment of synapses. We found more than 30 ALS-associated proteins in synaptoneurosomes, including TDP-43, FUS, SOD1 and C9ORF72. We identified almost 500 proteins with altered expression levels in ALS, with region-specific changes highlighting proteins and pathways with intriguing links to neurophysiology and pathology. Stratifying the ALS cohort by cognitive status revealed almost 150 specific alterations in cognitively impaired ALS synaptic preparations. Stratifying by C9ORF72-RE status revealed 330 protein alterations in the C9ORF72-RE +ve group, with KEGG pathway analysis highlighting strong enrichment for postsynaptic dysfunction, related to glutamatergic receptor signalling. We have validated some of these changes by western blot and at a single synapse level using array tomography imaging. In summary, we have generated the first unbiased map of the human ALS synaptic proteome, revealing novel insight into this key compartment in ALS pathophysiology and highlighting the influence of cognitive decline and C9ORF72-RE on synaptic composition.
... TDP-43 is involved in all aspects of RNA metabolism ranging from splicing, transcription, transport, storage into RNA/protein granules, and translation. Accumulating evidence has demonstrated that dysregulation of RNA metabolism contributes to ALS pathogenesis [7,74]. With the advancement of new technologies, including RNA sequencing, the link between TDP-43 pathology and RNA homeostasis is being extensively uncovered. ...
TAR DNA binding protein 43 (TDP-43) is a DNA/RNA binding protein involved in pivotal cellular functions, especially in RNA metabolism. Hyperphosphorylated and ubiquitinated TDP-43-positive neuronal cytoplasmic inclusions are identified in the brain and spinal cord in most cases of amyotrophic lateral sclerosis (ALS) and a substantial proportion of frontotemporal lobar degeneration (FTLD) cases. TDP-43 dysfunctions and cytoplasmic aggregation seem to be the central pathogenicity in ALS and FTLD. Therefore, unraveling both the physiological and pathological mechanisms of TDP-43 may enable the exploration of novel therapeutic strategies. This review highlights the current understanding of TDP-43 biology and pathology, describing the cellular processes involved in the pathogeneses of ALS and FTLD, such as post-translational modifications, RNA metabolism, liquid–liquid phase separation, proteolysis, and the potential prion-like propagation propensity of the TDP-43 inclusions.
... The two RRM domains preferentially recognize UG/TG-rich single-stranded or double-stranded DNA/RNA and have a variety of functions in mRNA stability mRNA transport, transcriptional inhibition, selective splicing of mRNA precursors and translation regulation [13,16,17,19,20]. RRMs and RNA polymerase II bind to DNA to form a transcription complex, which takes participate in gene edit for alternative splicing, remove, link or skip exons, such as CFTR exon9 and SMN exon7 [11,15,[21][22][23]. In addition, RRMs are recruited to bind to DNA acting on classical non-homologous end junction (NHEJ) DNA repair. ...
... Liquid-liquid phase separation (LLPS) is the process that TDP-43 is physiochemically separated from the surrounding environment under physiological conditions to form gelatinized membraneless organelles and to aggregate and fuse with each other. As a scaffold in the LLPS process of TDP-43, the longer RNA binds multiple RRMs to form a high-order structure droplet, while shorter RNA binds to fewer RRMs to resist LLPS [21]. This may represent an intermediate step between soluble and aggregated TDP-43. ...
... When the RNA/TDP-43 ratio is increased, TDP-43 inhibited self-aggregation by binding RNA, resulting in a decrease in the distribution density of RNA granules [14,30]. RNA granules are formed by recruiting ubiquitinated or phosphorylated TDP-43 and further formed stress granules after LLPS [21]. Under physiological conditions, LLPS and stress granules are dynamically reversible [31]. ...
In recent years, more and more neurodegenerative diseases, such as ALS, FTLD and AD, have been found to share a common pathological feature, which is the depletion of TDP-43 in the nucleus and the accumulation of TDP-43 in the cytoplasm through hyperphosphorylation, ubiquitination and cleavage. Therefore, this kind of neurodegenerative disease is also called TDP-43 proteinopathy. This suggests that TDP-43 plays a role in the pathogenesis of disease. Current studies show that the pathophysiological mechanism of TDP-43 in neurodegeneration is very complex. In this review, we describe the structure of TDP-43, its main physiological functions, the possible pathogenesis and how TDP-43 provides a new pathway to treat neurodegenerative diseases.
