Impaired slow axonal transport in diabetic peripheral nerve is independent of RAGE.
Diabetic peripheral nerve dysfunction is a common complication occurring in 30-50% of long-term diabetic patients. The pathogenesis of this dysfunction remains unclear but growing evidence suggests that it might be attributed, in part, to alteration in axonal transport. Our previous studies demonstrated that RAGE (Receptor for Advanced Glycation Endproducts) contributes to the pathogenesis of diabetic peripheral neuropathy and impairs nerve regeneration consequent to sciatic nerve crush, particularly in diabetes. We hypothesize that RAGE plays a role in axonal transport impairment via the interaction of its cytoplasmic domain with mammalian Diaphanous 1 (mDia1) - actin interacting molecule. Studies showed that mDia1-RAGE interaction is necessary for RAGE-ligand-dependent cellular migration, AKT phosphorylation, macrophage inflammatory response and smooth muscle migration. Here, we studied RAGE, mDia1 and markers of axonal transport rates in the peripheral nerves of wild-type C57BL/6 and RAGE null control and streptozotocin-injected diabetic mice at 1, 3 and 6 h after sciatic nerve crush. The results show that in both control and diabetic nerves, the amount of RAGE accumulated at the proximal and distal side of the crush area is similar, indicating that the recycling rate for RAGE is very high and that it is evenly transported from and towards the neuronal cell body. Furthermore, we show that slow axonal transport of proteins such as Neurofilament is affected by diabetes in a RAGE-independent manner. Finally, our study demonstrates that mDia1 axonal transport is impaired in diabetes, suggesting that diabetes-related changes affecting actin binding proteins occur early in the course of the disease.
Department of Surgery, Columbia University Medical Center, New York, NY, USA; Diabetes Research Center, Department of Medicine, NYU Langone Medical Center, Smilow Building 906, 550 First Avenue, New York, NY, 10016, USA.
Judyta K
JK
Juranek
Matthew S
MS
Geddis
Rosa
R
Rosario
Ann Marie
AM
Schmidt
D000818:Animals; D001370:Axonal Transport; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D000080865:Formins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009409:Nerve Crush; D016900:Neurofilament Proteins / Q000378:metabolism; D011485:Protein Binding; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012584:Sciatic Nerve / Q000378:metabolism* / Q000473:pathology
D002352:Carrier Proteins; C491464:Diap1 protein, mouse; D000080865:Formins; D016900:Neurofilament Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic
RAGE; axonal transport; diabetes; mDia1; mice