FIGURE SUMMARY
Title

Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects

Authors
de Calbiac, H., Renault, S., Haouy, G., Jung, V., Roger, K., Zhou, Q., Campanari, M.L., Chentout, L., Demy, D.L., Marian, A., Goudin, N., Edbauer, D., Guerrera, C., Ciura, S., Kabashi, E.
Source
Full text @ Autophagy
Figure 1.

C9orf72 knockdown is essential to trigger poly(GP) toxicity, inducing paralysis due to motor neuron degeneration.
Figure 2.

Poly(GP) and Sqstm1/p62 accumulate preferentially in motor neurons under c9orf72 knockdown.
Figure 3.

Autophagy induction rescues the synergistic toxicity of C9orf72 gain and loss of function.
Figure 4.

Proteomics indicates deficit in mitochondria function in motor neurons of C9orf72 gain and loss of function zebrafish.
Figure 5.

Mitophagy is altered under the synergistic effects of C9orf72 gain and loss of function.
Figure 6.

C9orf72 pathology induces motor neurons apoptosis.
Figure 7.

Proposed mechanisms for poly(GP) toxicity in C9orf72 haploinsufficiency. C9orf72 knockdown induces poly(GP) and SQSTM1/p62 accumulation in motor neurons due to autophagy alteration. These synergistic effects of C9orf72 loss of function and poly(GP) expression perturb mitochondrial homeostasis, including mitophagy deregulation. Subsequently, accumulated abnormal mitochondria engage the cell death cascade through cascade activation, finally resulting in motor neuron degeneration through apoptosis cell death and arising motor deficits. Several drugs have been identified as being able to counteract motor deficits in this C9orf72 model: the MTOR inhibitor rapamycin and the PIKFYVE inhibitor apilimod, both by activating autophagy; the mitophagy activator urolithin A; and decylubiquinone, an analogue of ubiquinone (coenzyme Q10) and inhibitor of mitochondrial depolarization.
Acknowledgments
This image is the copyrighted work of the attributed author or publisher, and ZFIN has permission only to display this image to its users. Additional permissions should be obtained from the applicable author or publisher of the image. Full text @ Autophagy
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