Slow Axonal Transport Impairment of Cytoskeletal Proteins in Streptozociti‐Induced Diabetic Neuropathy

Abstract

The impairment of slow axonal transport of cytoskeletal proteins was studied in the sciatic nerves of streptozocin-diabetic rats. [35S]Methionine was unilaterally injected into the fourth lumbar ganglion and spinal cord, to label the sensory and motor axons, respectively, and then the polymerized elements of the cytoskeleton and the corresponding soluble proteins were analyzed separately. In addition, the pellet/supernatant ratio for tubulin and actin was also assessed. Our results indicate that the velocity of slow component a (SCa) of axonal transport, particularly that of neurofilaments, was strongly reduced (by 60%) in sensory axons. At the same time, a decreased pellet/supernatant ratio of tubulin, possibly owing to a depolymerization of stable microtubules, was also observed. The transport of slow component b (SCb) of axonal transport was also impaired, but the extent of this impairment could not be precisely evaluated. In contrast, motor axons showed little or no impairment of both SCa and SCb at the time studied, a result suggesting a delayed development of the neuropathy in motor axons.

Experimental Diabetic Neuropathy: Effect of Ganglioside Treatment on Axonal Transport of Cytoskeletal Proteins

“…In addition, several studies emphasize that the axonal transport is affected more precociously and to a greater extent in sensory fibers of peripheral nerves than in motor fibers (7,10,11). These experimental findings correlate well with the clinical symptoms and signs in human diabetic polyneuropathy, in which sensory deficits occur earlier in the course of the disease.…”

“…Many reports indicate that the transport rate of some cytoskeletal proteins is affected in the nerve fibers of diabetic animals (5)(6)(7). Axonal transport of molecules and organelles either synthesized or assembled in the perikaryon is crucial to the maintenance of the structural and functional integrity of axons and synaptic terminals (8).…”

Neurotrophin-3 Prevents the Proximal Accumulation of Neurofilament Proteins in Sensory Neurons of Streptozocin-Induced Diabetic Rats

“…Furthermore, postnatal deletion of KIF-5A, a neuronal-specific kinesin, results in impaired axonal transport of neurofilament and induces accumulation in sensory neuron cell bodies and axonal shrinkage in dorsal root (37). The energy dependency of kinesin-associated cargo motility, coupled with the mitochondrial dysfunction (38,39) and energy deficiency (40) characteristic of diabetes, may therefore explain impaired protein transport observed in STZ-induced diabetes (6). Mechanism of NT-3-dependent prevention of neurofilament accumulation.…”

“…In the streptozocin (STZ) and BB rodent models of type 1 diabetes, structural abnormalities in peripheral nerve include decreased axonal caliber or axonal dwindling (1)(2)(3). Studies in type 1 diabetic rats show reduced expression of neurofilaments in sensory neurons (1,4,5), reduced axonal transport of neurofilament in sensory axons (6), loss of neurofilament in distal nerve (1)(2)(3)7), and abnormal neurofilament phosphorylation in the dorsal root ganglia (DRG), spinal cord, and sciatic nerve (8 -11). Aberrant phosphorylation of NF-H and NF-M subunits in DRG of STZ-and BB-diabetic rats is associated with activation of c-jun NH 2 -terminal kinase (JNK) (10).…”

Cytoskeleton, Axonal Transport, and the Mechanisms of Axonal Neuropathy

“…Similarly, in streptozotocin (STZ)-treated rats (a model of type I diabetes), slow axonal transport of neurofilament and microtubule components is also reduced and results in decreased axonal caliber (Medori et al, 1988). Interestingly, the impairment of axonal transport in diabetic nerves is more significant in sensory than in motor fibers (Macioce et al, 1989), which is consistent with the sensory predominant neuropathy observed in patients with diabetes.…”