Presenilin mutations deregulate mitochondrial Ca2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans
- Albany Medical College, United States
- Skidmore College, United States
Figures
Figure 2
SEL-12 is required for mitochondrial structural maintenance and mechanosensation.
(A) Representative images and quantification of the incidence of discontinuous ALM neuronal mitochondria. Analysis was done using transgenic animals expressing mCherry fused with the outer …
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Figure 2—source data 1
Raw data for Figure 2.
- https://doi.org/10.7554/eLife.33052.004
Figure 3 with 1 supplement
Loss of SEL-12 function results in neurodegeneration.
(A) Representative images of normal ALM neuronal soma and abnormal soma with ectopic sprouting (above), cartoon depicting location of ALM and PLM neuron in C. elegans (middle) and representative …
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Figure 3—source data 1
Raw data for Figure 3.
- https://doi.org/10.7554/eLife.33052.007
Figure 3—figure supplement 1
SEL-12 has a tissue-specific but protease independent role in neuronal health maintenance.
(A) Quantification of aberrant structures (sprouts/branches) in ALM neurons of day one sel-12(ty11) animals with tissue specific SEL-12 expression. ALM neuronal morphology analysis is done using …
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Figure 3—figure supplement 1—source data 1
Raw data for Figure 3—figure supplement 1.
- https://doi.org/10.7554/eLife.33052.008
Figure 4 with 1 supplement
Notch signaling and gamma-secretase activity is not required for mechanosensation or mechanosensory neuron morphology.
(A) Quantification of the response of Notch mutants (glp-1 and lin-12 mutants) to light anterior and posterior touch at day 1, 2 and 3 of adulthood. (B) Quantification of response to light touch in …
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Figure 4—source data 1
Raw data for Figure 4.
- https://doi.org/10.7554/eLife.33052.011
Figure 4—figure supplement 1
Loss of gamma-secretase function does not result in neurodegenerative morphologies.
(A) Quantification of aberrant structures (sprouts/branches) on ALM neuronal soma of wild type, sel-12(ty11) and sel-12(ty11) animals expressing wild type or a protease dead SEL-12 at day 1 of …
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Figure 4—figure supplement 1—source data 1
Raw data for Figure 4—figure supplement 1.
- https://doi.org/10.7554/eLife.33052.012
Figure 5 with 1 supplement
Expression of human Abeta1-42 peptide in the the nervous system results in functional loss dissimilar from sel-12 mutants.
(A) Quantification of the response of Abeta peptide expressing animals to light anterior and posterior touch at day 1 of adulthood. (B) Quantification of aberrant structures (sprouts/branches) on …
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Figure 5—source data 1
Raw data for Figure 5.
- https://doi.org/10.7554/eLife.33052.015
Figure 5—figure supplement 1
Western analysis of pan-neuronal expression of Abeta1-42 in C. elegans.
(A) Representative western blot indicating Abeta1-42 peptide accumulation in the pan-neuronal Abeta1-42 expressing strain CL2355. * indicate non specific bands as observed in wild type animals. (B) …
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Figure 5—figure supplement 1—source data 1
Raw data for Figure 5—figure supplement 1.
- https://doi.org/10.7554/eLife.33052.016
Figure 1 with 1 supplement
Mutations in sel-12 and PSEN1 result in higher rates of oxygen consumption and generate higher levels of ATP.
(A) Quantification of mitochondrial Ca2+ using animals expressing mito::GCaMP6 and mCherry in their body wall muscle (takEx347). (B) Quantification of the relative ATP levels in sel-12 mutants …
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Figure 1—source data 1
Raw data for Figure 1.
- https://doi.org/10.7554/eLife.33052.019
Figure 1—figure supplement 1
Mitochondrial Ca2+levels are higher in sel-12 mutants.
(A) Representative image of mito-GCaMP6 and mCherry expression (takEx347). Scale bar represents 10 μm. (B) Quantification of mitochondrial Ca2+ using animals expressing mito::GCaMP6 and mCherry in …
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Figure 1—figure supplement 1—source data 1
Raw data for Figure 1—figure supplement 1.
- https://doi.org/10.7554/eLife.33052.020
Figure 6 with 2 supplements
Reducing ER Ca2+release in sel-12 mutants rescues mitochondrial disorganization and dysfunction, ectopic neurite sprouting and mechanosensory defects.
(A) Quantification of mitochondrial Ca2+ using animals expressing mito::GCaMP6 and mCherry in their body wall muscle (takEx347). n = 30 per strain. (B) Representative images and (C) quantification …
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Figure 6—source data 1
Raw data for Figure 6.
- https://doi.org/10.7554/eLife.33052.024
Figure 6—figure supplement 1
Loss of ryanodine receptors results in the improvement of neurodegeneration in sel-12 null animals.
(A) Quantification of mitochondrial Ca2+ using animals expressing mito::GCaMP6 and mCherry in their mechanosensory neurons (takEx415). (B) Basal and (C) maximal respiration rates of wild type, sel-12…
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Figure 6—figure supplement 1—source data 1
Raw data for Figure 6—figure supplement 1.
- https://doi.org/10.7554/eLife.33052.025
Figure 6—figure supplement 2
Reduction of ER Ca2+ release improves the structure of mechanosensory neurons in sel-12 animals.
Quantification of the frequency of (A) wave-like processes, (B) lesions and (C) breaks in ALM and PLM neuronal processes in wild type, sel-12(ty11) and crt-1;sel-12(ty11) animals at day 1 of …
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Figure 6—figure supplement 2—source data 2
Raw data for Figure 6—figure supplement 2.
- https://doi.org/10.7554/eLife.33052.026
Figure 7 with 1 supplement
PSEN functions to regulate mitochondrial activity by mediating Ca2+ transfer from the ER to the mitochondria.
(A) Quantification of mitochondrial Ca2+ using animals expressing mito::GCaMP6 and mCherry in their body wall muscle (takEx347). (B) Quantification of ALM neuronal mitochondrial morphology. Analysis …
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Figure 7—source data 1
Raw data for Figure 7.
- https://doi.org/10.7554/eLife.33052.029
Figure 7—figure supplement 1
Reduction of ER Ca2+ release improves the structure of mechanosensory neurons in sel-12 animals.
Quantification of (A) wavelike processes, (B) lesions and (C) breaks in ALM and PLM neuronal processes in wild type, sel-12(ty11) and mcu-1;sel-12(ty11) animals at day 1 of adulthood. Neuronal …
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Figure 7—figure supplement 1—source data 1
Raw data for Figure 7—figure supplement 1.
- https://doi.org/10.7554/eLife.33052.030
Figure 8 with 1 supplement
Reducing mitochondrial activity using doxycyline alleviates neurodegenerative phenotypes observed in sel-12 mutants.
(A) Basal and (B) maximal respiration rates of wild type and sel-12 mutant animals treated with doxycycline (dox). (C) Quantification of the response of dox treated day one sel-12(ty11) animals to …
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Figure 8—source data 1
Raw data for Figure 8.
- https://doi.org/10.7554/eLife.33052.033
Figure 8—figure supplement 1
Reduction of mitochondrial fission does not alleviate the neurodegeneration in sel-12(ty11) animals.
(A) Quantification of ALM neuronal mitochondrial morphology in sel-12(ty11) animals grown on EV and drp-1(RNAi). Analysis was done using transgenic animals expressing mito::GFP in mechanosensory …
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Figure 8—figure supplement 1—source data 1
Raw data for Figure 8—figure supplement 1.
- https://doi.org/10.7554/eLife.33052.034
Figure 9 with 1 supplement
MitoTEMPO supplementation improves neuronal structure and function of sel-12 mutants.
(A) Quantification of oxidized state of ALM neuronal mitochondria using zhsEx17 [Pmec-4mitoLS::ROGFP] (B) Quantification of aberrant neuronal structures (sprouts/branches) in ALM neurons in day one …
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Figure 9—source data 1
Raw data for Figure 9.
- https://doi.org/10.7554/eLife.33052.037
Figure 9—figure supplement 1
Mitochondrial disorganization in the mechanosensory neurons of sel-12 animals is not a direct result of elevated ROS levels.
(A) Quantification of oxidized state of ALM neuronal mitochondria using zhsEx17 [Pmec-4mitoLS::ROGFP] treated with TPP or mitoTEMPO. (B) Quantification of mitochondrial Ca2+ using animals expressing …
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Figure 9—figure supplement 1—source data 1
Raw data for Figure 9—figure supplement 1.
- https://doi.org/10.7554/eLife.33052.038
Additional files
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Transparent reporting form
- https://doi.org/10.7554/eLife.33052.039
