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PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS

B. Nieuwenhuis, AC. Barber, RS. Evans, CS. Pearson, J. Fuchs, AR. MacQueen, S. van Erp, B. Haenzi, LA. Hulshof, A. Osborne, R. Conceicao, TZ. Khatib, SS. Deshpande, J. Cave, C. Ffrench-Constant, PD. Smith, K. Okkenhaug, BJ. Eickholt, KR. Martin,...

. 2020 ; 12 (8) : e11674. [pub] 20200617

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc21026614

Grantová podpora
BBS/E/B/000C0427 UK Research and Innovation Biotechnology and Biological Sciences Research Council (BBSRC) - International
CZ.02.1.01/0.0./0.0/15_003/0000419 Czech Ministry of Education, Centre of Reconstructive Neuroscience - International
SFB TRR 186 Deutsche Forschungsgemeinschaft (DFG) - International
MR/R004544/1 Medical Research Council - United Kingdom
MR/R004544/1 UK Research and Innovation, Medical Research Council (MRC) - International
ALTF 1436-2015 European Molecular Biology Organization (EMBO) - International
5065/5066 Fight for Sight UK - International
TP10 Deutsche Forschungsgemeinschaft (DFG) - International
SFB 958 Deutsche Forschungsgemeinschaft (DFG) - International
MR/K017047/1 Medical Research Council - United Kingdom
MRC Sackler - International
BBS/E/B/000C0409 Biotechnology and Biological Sciences Research Council - United Kingdom
G0300336 Medical Research Council - United Kingdom
MR/R004463/1 Medical Research Council - United Kingdom
Cambridge Eye Trust - International
Christopher and Dana Reeve Foundation (Reeve Foundation) - International
ERA-NET Neuron grant AxonRepair - International
Multiple Sclerosis Society (MS Society) - International
5119/5120 Fight for Sight UK - International
MR/R004463/1 UK Research and Innovation, Medical Research Council (MRC) - International
095691/Z/11/Z Wellcome Trust (WT) - International
National Eye Research Centre (NERC) - International
TP16 Deutsche Forschungsgemeinschaft (DFG) - International
NRB110 International Spinal Research Trust - International

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 (PIP3 ). We demonstrate that adult PNS neurons utilise two catalytic subunits of PI3K for axon regeneration: p110α and p110δ. However, in the CNS, axonal PIP3 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 PIP3 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 PIP3 as a key reason for intrinsic regeneration failure and demonstrate that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion.

Citace poskytuje Crossref.org

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