Impaired slow axonal transport in diabetic peripheral nerve is independent of RAGE

Abstract

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.

Mechanisms of distal axonal degeneration in peripheral neuropathies

“…The expression and modification of these cytoskeletal proteins (actin, neurofilament, tubulin) is believed to interfere with cytoskeletal assembly, and, thus, axonal transport [163]. RAGE is predicted to interactwith actin through its effector mDia1[124, 129, 157], but recent work has elegantly shown that slowed axonal transport in diabetic animals is independent of RAGE expression [129]. Despite the slowed transport of the RAGE/actin effector protein mDia1 in diabetic animals (wild type and RAGE knockout), RAGE itself was not differentially present between diabetic and control animals.…”

Axonal transport of cytoskeleton and cytoskeleton regulatory cargo proteins in neurodegenerative disorders

“…Time-lapse experiments revealed that the average rate of neurofilament transport is that of fast axonal transport but it is delayed by continuous pauses for prolonged periods of time 30 ; this breakthrough observation laid ground for the current view of neurofilament transportation in the nervous system and provided insight into general mechanisms governing cytoskeletal protein cargo transportation. Even before that discovery, irrespective of the nature of neurofilament axonal transport, many authors noted that its impairment may contribute to the pathogenesis of neurodegenerative diseases such as: ALS [31][32][33][34] , Charcot-Marie-Tooth 19,38 . Impairment of neurofilament axonal transport might be caused by mutations/ change of function of transport proteins (indirect cause) or by changes in the neurofilament structure and/ or function (direct cause).…”

“…Another study, conducted in Alzheimer's model PS1/APP mice, revealed that the presence of phosphorylated tau protein affects molecular motors and the actin cytoskeleton, likely leading to alternations of axonal transport and abnormal metabolism of these proteins 58 . Observed impairment in actin axonal transport might be also contributed, as in case of neurofilament, to increased levels of glycation leading to subsequent changes in actin chemical structure that affect axonal transport 19,61 .…”

“…: a) adultonset neurodegenerative diseases, AONDs 4,5 , a set of dysfunctional and degenerative disorders affecting different populations of neurons; b) motor neuron disorders such as: amyotrophic lateral sclerosis 6,7 , distal hereditary motor neuropathy 8 , spinal muscular atrophy 7 , hereditary spastic paraplegia 9 ; c) Alzheimer's, Parkinson's and Huntington's and related disorders [10][11][12][13] ; and d) Charcot-Marie-Tooth disease (CMT), a heterogeneous group of hereditary motor and sensory neuropathies 1,14 . Recently, disturbances in axonal transport have also been shown in neurological complications of diabetes [15][16][17][18][19] . Molecular mechanisms underlying axonal transport deficiencies vary between diseases and might be divided into four categories related to dysfunction of: 1) molecular motors (kinesin and dynein) 2) microtubules, 3) cargoes and 4) mitochondria.…”

“…Pathological, post-translational changes of neurofilament structure, such as extensive phosphorylation [46][47][48] and nonenzymatic glycation 46,49,50 have also been shown to affect neurofilament transport, resulting in neurofilament accumulation and consequently altering axonal structure and function leading to nerve degeneration. Recent experiments focused on axonal transport impairment in the diabetic peripheral nerve revealed that neurofilament transport is indeed delayed and this delay coincides with the increased level of Carboxymethyllysine (CML), an advanced glycation end-product (AGE) indicative of high levels of glycation likely affecting neurofilament structure 19 . in which they were performed.…”