PI 3-kinase delta enhances axonal PIP 3 to support axon regeneration in the adult CNS.

Autor: Nieuwenhuis B; John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.; Laboratory for Regeneration of Sensorimotor Systems, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands., Barber AC; John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Evans RS; John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Pearson CS; John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Fuchs J; Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany., MacQueen AR; Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, UK., van Erp S; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK., Haenzi B; John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Hulshof LA; John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Osborne A; John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Conceicao R; John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Khatib TZ; John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Deshpande SS; John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Cave J; John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Ffrench-Constant C; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK., Smith PD; Department of Neuroscience, Carleton University, Ottawa, ON, Canada., Okkenhaug K; Department of Pathology, University of Cambridge, Cambridge, UK., Eickholt BJ; Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany., Martin KR; John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Vic., Australia.; Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Vic., Australia., Fawcett JW; John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.; Centre of Reconstructive Neuroscience, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Czech Republic., Eva R; John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2020 Aug 07; Vol. 12 (8), pp. e11674. Date of Electronic Publication: 2020 Jun 17.
DOI: 10.15252/emmm.201911674
Abstrakt: Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ). We demonstrate that adult PNS neurons utilise two catalytic subunits of PI3K for axon regeneration: p110α and p110δ. However, in the CNS, axonal PIP 3 decreases with development at the time when axon transport declines and regenerative competence is lost. Overexpressing p110α in CNS neurons had no effect; however, expression of p110δ restored axonal PIP 3 and increased regenerative axon transport. p110δ expression enhanced CNS regeneration in both rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110α. Furthermore, viral delivery of p110δ promoted robust regeneration after optic nerve injury. These findings establish a deficit of axonal PIP 3 as a key reason for intrinsic regeneration failure and demonstrate that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion.
(© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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