2020
DOI: 10.1038/s41467-020-14815-x
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Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons

Abstract: Cytoplasmic aggregation of TDP-43 characterizes degenerating neurons in most cases of amyotrophic lateral sclerosis (ALS). Here, we develop an optogenetic TDP-43 variant (opTDP-43), whose multimerization status can be modulated in vivo through external light illumination. Using the translucent zebrafish neuromuscular system, we demonstrate that short-term light stimulation reversibly induces cytoplasmic opTDP-43 mislocalization, but not aggregation, in the spinal motor neuron, leading to an axon outgrowth defe… Show more

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Cited by 70 publications
(85 citation statements)
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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%
See 1 more Smart Citation
“…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%
“…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%
“…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%