TY - JOUR
T1 - Hyperactive delta isoform of PI3Kinase enables long distance regeneration of adult rat corticospinal tract
AU - Kristyna, Karova
AU - Zuzana, Polcanova
AU - Lydia, Knight
AU - Stepanka, Suchankova
AU - Bart, Nieuwenhuis
AU - Radovan, Holota
AU - Vit, Herynek
AU - Lucia, Machova Urdzikova
AU - Rostislav, Turecek
AU - Jessica, Kwok C
AU - van den Herik, Joelle
AU - Verhaagen, Joost
AU - Richard, Eva
AU - James, Fawcett W
AU - Pavla, Jendelova
N1 - Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2025/1/1
Y1 - 2025/1/1
N2 - Neurons in the central nervous system (CNS) lose regenerative potential with maturity, leading to minimal corticospinal tract (CST) axon regrowth after spinal cord injury (SCI). In young rodents, knockdown of PTEN, which antagonises PI3K signalling by hydrolysing PIP3, promotes axon regeneration following SCI. However, this effect diminishes in adults, potentially due to lower PI3K activation leading to reduced PIP3. This study explores if increased PIP3 generation can promote long-distance regeneration in adults. We used a hyperactive PI3K, PI3Kδ (PIK3CD), to boost PIP3 levels in mature cortical neurons and assessed CST regeneration after SCI. Adult rats received AAV1-PIK3CD and AAV1-eGFP, or AAV1-eGFP alone, in the sensorimotor cortex concurrent with a C4 dorsal SCI. Transduced neurons showed increased pS6 levels, indicating elevated PI3K/Akt/mTOR signalling. CST regeneration, confirmed with retrograde tracing, was evaluated up to 16 weeks post-injury. At 12 weeks, ∼100 axons were present at lesion sites, doubling to 200 by 16 weeks, with regeneration indices of 0.1 and 0.2, respectively. Behavioural tests showed significant improvements in paw reaching, grip strength, and ladder rung walking in PIK3CD-treated rats, corroborated by electrophysiological recordings of cord dorsum potentials and distal flexor muscles EMG. Thus, PI3Kδ upregulation in adult cortical neurons enhances axonal regeneration and functional recovery post-SCI.
AB - Neurons in the central nervous system (CNS) lose regenerative potential with maturity, leading to minimal corticospinal tract (CST) axon regrowth after spinal cord injury (SCI). In young rodents, knockdown of PTEN, which antagonises PI3K signalling by hydrolysing PIP3, promotes axon regeneration following SCI. However, this effect diminishes in adults, potentially due to lower PI3K activation leading to reduced PIP3. This study explores if increased PIP3 generation can promote long-distance regeneration in adults. We used a hyperactive PI3K, PI3Kδ (PIK3CD), to boost PIP3 levels in mature cortical neurons and assessed CST regeneration after SCI. Adult rats received AAV1-PIK3CD and AAV1-eGFP, or AAV1-eGFP alone, in the sensorimotor cortex concurrent with a C4 dorsal SCI. Transduced neurons showed increased pS6 levels, indicating elevated PI3K/Akt/mTOR signalling. CST regeneration, confirmed with retrograde tracing, was evaluated up to 16 weeks post-injury. At 12 weeks, ∼100 axons were present at lesion sites, doubling to 200 by 16 weeks, with regeneration indices of 0.1 and 0.2, respectively. Behavioural tests showed significant improvements in paw reaching, grip strength, and ladder rung walking in PIK3CD-treated rats, corroborated by electrophysiological recordings of cord dorsum potentials and distal flexor muscles EMG. Thus, PI3Kδ upregulation in adult cortical neurons enhances axonal regeneration and functional recovery post-SCI.
U2 - 10.1016/j.ymthe.2024.12.040
DO - 10.1016/j.ymthe.2024.12.040
M3 - Article
C2 - 39748509
SN - 1525-0016
VL - 33
SP - 1
EP - 19
JO - Molecular Therapy
JF - Molecular Therapy
ER -