Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons

Asakawa, Kazuhide; Handa, Hiroshi; Kawakami, Koichi

doi:10.1038/s41467-020-14815-x

Cited by 66 publications

(82 citation statements)

References 66 publications

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“…Yet systemic stress makes it difficult to differentiate phenotypes associated with TDP-43 mislocalization and accumulation to general cellular stress responses. To overcome this limitation, a novel model expressed TDP-43 fused with an Arabidopsis thaliana-derived Cryptochrome 2 (CRY2) protein to allow for optogenetic instigation of LLPS [108,109,111,165]. In contrast to prolonged sodium arsenite treatment, prolonged LLPS through optogenetic stimulation in wild-type conditions results in TDP-43 inclusions within the nucleus absent of ALS hallmarks including hyperphosphorylation and SQSTM1 sequestration [108].…”

Section: Additional Avenues Of Tdp-43 Toxicitymentioning

confidence: 99%

“…As TDP-43 can readily undergo phase separation, the increase in cytoplasmic density biophysically promotes LLPS to occur (reviewed by Boeynaems et al [98]). This is apparent in models of cellular stress when TDP-43 is mislocalized as there is a significant increase in the cellular stress response including rapid formation of stress granules and TDP-43 granules [109,111,165]. Therefore, mislocalization may sensitize the cell to respond disproportionately to a cellular stress than it may normally be less responsive to.…”

Section: The Contribution Of Tdp-43 Mislocalization To Cellular Toxicmentioning

confidence: 99%

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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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Section: Additional Avenues Of Tdp-43 Toxicitymentioning

confidence: 99%

Section: The Contribution Of Tdp-43 Mislocalization To Cellular Toxicmentioning

confidence: 99%

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Suk

Rousseaux

2020

Mol Neurodegeneration

208

170

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“…ALS causative gene products, including FUS, TIA-1, and, of course, TDP-43, are proposed to form aggregates via LLPS. Consistent with this hypothesis, recent studies have discovered that optical multimerization of cytoplasmic TDP-43 induces the aggregation and sequestration of endogenous nuclear TDP-43 into the cytoplasmic aggregates that are dependent on LLPS 16,17 .…”

Section: Introductionmentioning

confidence: 75%

Aggresome formation and liquid–liquid phase separation independently induce cytoplasmic aggregation of TAR DNA-binding protein 43

et al. 2020

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Cytoplasmic inclusion of TAR DNA-binding protein 43 (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and a subtype of frontotemporal lobar degeneration (FTLD). Recent studies have suggested that the formation of cytoplasmic TDP-43 aggregates is dependent on a liquid–liquid phase separation (LLPS) mechanism. However, it is unclear whether TDP-43 pathology is induced through a single intracellular mechanism such as LLPS. To identify intracellular mechanisms responsible for TDP-43 aggregation, we established a TDP-43 aggregation screening system using a cultured neuronal cell line stably expressing EGFP-fused TDP-43 and a mammalian expression library of the inherited ALS/FTLD causative genes, and performed a screening. We found that microtubule-related proteins (MRPs) and RNA-binding proteins (RBPs) co-aggregated with TDP-43. MRPs and RBPs sequestered TDP-43 into the cytoplasmic aggregates through distinct mechanisms, such as microtubules and LLPS, respectively. The MRPs-induced TDP-43 aggregates were co-localized with aggresomal markers and dependent on histone deacetylase 6 (HDAC6), suggesting that aggresome formation induced the co-aggregation. However, the MRPs-induced aggregates were not affected by 1,6-hexanediol, an LLPS inhibitor. On the other hand, the RBPs-induced TDP-43 aggregates were sensitive to 1,6-hexanediol, but not dependent on microtubules or HDAC6. In sporadic ALS patients, approximately half of skein-like TDP-43 inclusions were co-localized with HDAC6, but round and granular type inclusion were not. Moreover, HDAC6-positive and HDAC6-negative inclusions were found in the same ALS patient, suggesting that the two distinct pathways are both involved in TDP-43 pathology. Our findings suggest that at least two distinct pathways (i.e., aggresome formation and LLPS) are involved in inducing the TDP-43 pathologies.

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“…Studies suggest that initiation of caspase-3/7 activation by TDP-43 toxicity facilitates the disease progression by cleaving mislocalized TDP-43 into 35 and 25 kDa fragments. These highly aggregation-prone fragments promote inclusion body formations with the hyperphosphorylated and polyubiquitinated C-terminal domain of TDP-43 [50,51]. In addition to the C-terminal fragment, full-length and homo-dimerized TDP-43 also has been identified in the spinal cord…”

Section: Familial and Sporadic Alsmentioning

confidence: 99%

The Role of TDP-43 in Genome Repair and beyond in Amyotrophic Lateral Sclerosis

Mitra

Hegde²

2020

Amyotrophic Lateral Sclerosis - Recent Advances and Therapeutic Challenges

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The pathology of the RNA-/DNA-binding protein TDP-43, first implicated a decade ago in the motor neuron disease amyotrophic lateral sclerosis (ALS), has been subsequently linked to a wide spectrum of neurodegenerative diseases, including frontotemporal dementia (FTD), Alzheimer's disease (AD), and related dementia-associated disorders. ALS, also known as Lou Gehrig's disease, is a progressive, degenerative motor neuron disorder, characterized by a diverse etiopathology. TDP-43 pathology, mediated by a combination of several mutations in the TARDBP gene and stress factors, has been linked to more than 97% of ALS patients. We recently identified, for the first time, the critical involvement of TDP-43 in neuronal genome maintenance and the repair of DNA double-strand breaks (DSBs). Our studies showed that TDP-43 regulates the DNA break-sealing activities of the XRCC4-DNA Ligase 4 (LIG4) complex in DSB repair, suggesting that loss of genomic integrity in TDP-43-associated neurodegeneration may be amenable to a DNA repair-based intervention. In this chapter, we discuss the broader aspects of TDP-43 toxicityinduced pathomechanisms, including the emerging role of TDP-43 in neuronal DSB repair and its synergistic genotoxic effects with other neurodegeneration-associated etiologies that contribute significantly to neuronal dysfunction. We also discuss potential future perspectives and underscore how unraveling the molecular basis and implications of TDP-43-induced genome instability in ALS could guide the development of neuroprotective therapies.

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Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons

Cited by 66 publications

References 66 publications

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Aggresome formation and liquid–liquid phase separation independently induce cytoplasmic aggregation of TAR DNA-binding protein 43

The Role of TDP-43 in Genome Repair and beyond in Amyotrophic Lateral Sclerosis

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