| Authors |
Singh B, Singh V, Krishnan A, Koshy K, Martinez JA, Cheng C, Almquist C,
Zochodne DW
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| Submitted By |
Douglas Zochodne on 5/5/2014 |
| Status |
Published |
| Journal |
Brain : a journal of neurology |
| Year |
2014 |
| Date Published |
4/1/2014 |
| Volume : Pages |
137 : 1051 - 1067 |
| PubMed Reference |
24578546 |
| Abstract |
Diabetes mellitus renders both widespread and localized irreversible damage to
peripheral axons while imposing critical limitations on their ability to
regenerate. A major failure of regenerative capacity thereby imposes a 'double
hit' in diabetic patients who frequently develop focal neuropathies such as
carpal tunnel syndrome in addition to generalized diffuse polyneuropathy. The
mechanisms of diabetic neuron regenerative failure have been speculative and few
approaches have offered therapeutic opportunities. In this work we identify an
unexpected but major role for PTEN upregulation in diabetic peripheral neurons
in attenuating axon regrowth. In chronic diabetic neuropathy models in mice, we
identified significant PTEN upregulation in peripheral sensory neurons of
messenger RNA and protein compared to littermate controls. In vitro, sensory
neurons from these mice responded to PTEN knockdown with substantial rises in
neurite outgrowth and branching. To test regenerative plasticity in a chronic
diabetic model with established neuropathy, we superimposed an additional focal
sciatic nerve crush injury and assessed morphological, electrophysiological and
behavioural recovery. Knockdown of PTEN in dorsal root ganglia ipsilateral to
the side of injury was achieved using a unique form of non-viral short
interfering RNA delivery to the ipsilateral nerve injury site and paw. In
comparison with scrambled sequence control short interfering RNA, PTEN short
interfering RNA improved several facets of regeneration: recovery of compound
muscle action potentials, reflecting numbers of reconnected motor axons to
endplates, conduction velocities of both motor and sensory axons, reflecting
their maturation during regrowth, numbers and calibre of regenerating myelinated
axons distal to the injury site, reinnervation of the skin by unmyelinated
epidermal axons and recovery of mechanical sensation. Collectively, these
findings identify a novel therapeutic approach, potentially applicable to other
neurological conditions requiring specific forms of molecular knockdown, and
also identify a unique target, PTEN, to treat diabetic neuroregenerative
failure.
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