CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage

Jichao Sun, Jared Carlson-Stevermer, Utpal Das, Minjie Shen, Marion Delenclos, Amanda M. Snead, So Yeon Koo, Lina Wang, Dianhua Qiao, Jonathan Loi, Andrew J. Petersen, Michael Stockton, Anita Bhattacharyya, Mathew V. Jones, Xinyu Zhao, Pamela J McLean, Andrew A. Sproul, Krishanu Saha, Subhojit Roy

Research output: Contribution to journalArticle

Abstract

CRISPR/Cas9 guided gene-editing is a potential therapeutic tool, however application to neurodegenerative disease models has been limited. Moreover, conventional mutation correction by gene-editing would only be relevant for the small fraction of neurodegenerative cases that are inherited. Here we introduce a CRISPR/Cas9-based strategy in cell and animal models to edit endogenous amyloid precursor protein (APP) at the extreme C-terminus and reciprocally manipulate the amyloid pathway, attenuating APP-β-cleavage and Aβ production, while up-regulating neuroprotective APP-α-cleavage. APP N-terminus and compensatory APP-homologues remain intact, with no apparent effects on neurophysiology in vitro. Robust APP-editing is seen in human iPSC-derived neurons and mouse brains with no detectable off-target effects. Our strategy likely works by limiting APP and BACE-1 approximation, and we also delineate mechanistic events that abrogates APP/BACE-1 convergence in this setting. Our work offers conceptual proof for a selective APP silencing strategy.

Original languageEnglish (US)
Article number53
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Clustered Regularly Interspaced Short Palindromic Repeats
editing
Amyloid beta-Protein Precursor
Protein C
Amyloid
cleavage
proteins
genes
neurophysiology
Genes
Neurophysiology
Neurodegenerative diseases
Serum Amyloid A Protein
animal models
mutations
neurons
Neurodegenerative Diseases
Neurons
brain
mice

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Sun, J., Carlson-Stevermer, J., Das, U., Shen, M., Delenclos, M., Snead, A. M., ... Roy, S. (2019). CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage. Nature Communications, 10(1), [53]. https://doi.org/10.1038/s41467-018-07971-8

CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage. / Sun, Jichao; Carlson-Stevermer, Jared; Das, Utpal; Shen, Minjie; Delenclos, Marion; Snead, Amanda M.; Koo, So Yeon; Wang, Lina; Qiao, Dianhua; Loi, Jonathan; Petersen, Andrew J.; Stockton, Michael; Bhattacharyya, Anita; Jones, Mathew V.; Zhao, Xinyu; McLean, Pamela J; Sproul, Andrew A.; Saha, Krishanu; Roy, Subhojit.

In: Nature Communications, Vol. 10, No. 1, 53, 01.12.2019.

Research output: Contribution to journalArticle

Sun, J, Carlson-Stevermer, J, Das, U, Shen, M, Delenclos, M, Snead, AM, Koo, SY, Wang, L, Qiao, D, Loi, J, Petersen, AJ, Stockton, M, Bhattacharyya, A, Jones, MV, Zhao, X, McLean, PJ, Sproul, AA, Saha, K & Roy, S 2019, 'CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage' Nature Communications, vol. 10, no. 1, 53. https://doi.org/10.1038/s41467-018-07971-8
Sun, Jichao ; Carlson-Stevermer, Jared ; Das, Utpal ; Shen, Minjie ; Delenclos, Marion ; Snead, Amanda M. ; Koo, So Yeon ; Wang, Lina ; Qiao, Dianhua ; Loi, Jonathan ; Petersen, Andrew J. ; Stockton, Michael ; Bhattacharyya, Anita ; Jones, Mathew V. ; Zhao, Xinyu ; McLean, Pamela J ; Sproul, Andrew A. ; Saha, Krishanu ; Roy, Subhojit. / CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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