Figure 7.

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.