Co-editing PINK1 and DJ-1 genes via AAV-delivered CRISPR/Cas9 system in adult monkey brains elicits classic Parkinsonian phenotypes

Li, H.; Wu, S.; Ma, X.; Li, X.; Cheng, T.; Chen, Z.; Wu, J.; Lv, L.; Li, L.; Xu, L.; Wang, W.; Hu, Y.; Jiang, H.; Yin, Y.; Qiu, Z.; Hu, X.

doi:10.1101/2020.09.19.305003

bioRxiv · 10.1101/2020.09.19.305003

Co-editing PINK1 and DJ-1 genes via AAV-delivered CRISPR/Cas9 system in adult monkey brains elicits classic Parkinsonian phenotypes

Li, H.·Wu, S.·Ma, X.·Li, X.·Cheng, T.·Chen, Z.·Wu, J.·Lv, L.·Li, L.·Xu, L.·Wang, W.·Hu, Y.·Jiang, H.·Yin, Y.·Qiu, Z.·Hu, X.

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Abstract

Whether direct manipulation of Parkinsons disease (PD) risk genes in monkey brain can elicit Parkinsonian phenotypes remains an unsolved issue. Here, we employed an adeno-associated virus (AAV)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigra (SN) region of four adult monkey brains. After the operation, two of the monkeys exhibited all classic PD symptoms, including bradykinesia, tremor, and postural instability, accompanied by severe nigral dopaminergic neuron loss (over 60%) and -synuclein pathology. The aged monkeys were more vulnerable to gene editing by showing faster PD progression, higher final total PD scores, and severer pathologic changes compared with their younger counterparts, suggesting both the genetic and aging factors played important roles in PD development. This gene editing system can be used to develop a large quantity of genetically edited PD monkeys over a short period, thus providing a practical transgenic monkey model for future PD studies.

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Li, H., Wu, S., Ma, X., Li, X., Cheng, T., Chen, Z., Wu, J., Lv, L., Li, L., Xu, L., Wang, W., Hu, Y., Jiang, H., Yin, Y., Qiu, Z., Hu, X.. 2020-09-20. Co-editing PINK1 and DJ-1 genes via AAV-delivered CRISPR/Cas9 system in adult monkey brains elicits classic Parkinsonian phenotypes. https://doi.org/10.1101/2020.09.19.305003

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