Failure to Upregulate the RNA Binding Protein ZBP After Injury Leads to Impaired Regeneration in a Rodent Model of Diabetic Peripheral Neuropathy.

James I Jones,Caitlin Cooney,Matthew Ponticiello,David C Goldberg,Wilfredo Mellado,Thong C Ma,Christopher J Costa,Melanie W Cohen,Dianna E Willis

doi:10.3389/fnmol.2021.728163

Abstract

Most diabetes patients eventually suffer from peripheral nerve degeneration. Unfortunately, there is no treatment for the condition and its mechanisms are not well understood. There is, however, an emerging consensus that the inability of peripheral nerves to regenerate normally after injury contributes to the pathophysiology. We have previously shown that regeneration of peripheral axons requires local axonal translation of a pool of axonal mRNAs and that the levels and members of this axonal mRNA pool are altered in response to injury. Here, we show that following sciatic nerve injury in a streptozotocin rodent model of type I diabetes, this mobilization of RNAs into the injured axons is attenuated and correlates with decreased axonal regeneration. This failure of axonal RNA localization results from decreased levels of the RNA binding protein ZBP1. Over-expression of ZBP1 rescues the in vitro growth defect in injured dorsal root ganglion neurons from diabetic rodents. These results provide evidence that decreased neuronal responsiveness to injury in diabetes is due to a decreased ability to alter the pool of axonal mRNAs available for local translation, and may open new therapeutic opportunities for diabetic peripheral neuropathy.

Highlights

Axonal injury in the peripheral nervous system (PNS) conditions neurons for more rapid axonal regeneration; these neurons show more rapid elongation after a subsequent injury (McQuarrie, 1978; Forman et al, 1980; McQuarrie and Grafstein, 1981; Lankford et al, 1998)
We have shown that regenerating axons of injury-conditioned (DRG) neurons are capable of local protein synthesis during rapid axonal regeneration (Willis et al, 2005, 2007)
The most distal targets of the smallest PNS axons are generally first affected in diabetic peripheral neuropathy (DPN) (Anand et al, 1994); the sheer distance separating the nerve ending from the cell body, coupled with the potential causes of DPN, may render PNS neurons less resistant to trauma in diabetes

Summary

Introduction

Axonal injury in the peripheral nervous system (PNS) conditions neurons for more rapid axonal regeneration; these neurons show more rapid elongation after a subsequent injury (McQuarrie, 1978; Forman et al, 1980; McQuarrie and Grafstein, 1981; Lankford et al, 1998). Reduced ZBP Attenuates Regeneration in DPN protein synthesis contribute to the targeting of proteins to specific sub-cellular domains of neurons, including the axonal compartment, which has the ability to locally generate new proteins. Our results show that several hundred mRNAs extend into adult rodent dorsal root ganglion (DRG) axons and that the breadth of axonally synthesized proteins is much more complex than initially predicted (Willis et al, 2005, 2007; Gumy et al, 2011). We have shown that regenerating axons of injury-conditioned (DRG) neurons are capable of local protein synthesis during rapid axonal regeneration (Willis et al, 2005, 2007). The results of these studies indicate that localized protein synthesis plays a critical role in axonal regeneration

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