Dynamic changes of neuroskeletal proteins in DRGs underlie impaired axonal maturation and progressive axonal degeneration in type 1 diabetes.
We investigated mechanisms underlying progressive axonal dysfunction and structural deficits in type 1 BB/Wor-rats from 1 week to 10 month diabetes duration. Motor and sensory conduction velocities were decreased after 4 and 6 weeks of diabetes and declined further over the remaining 9 months. Myelinated sural nerve fibers showed progressive deficits in fiber numbers and sizes. Structural deficits in unmyelinated axonal size were evident at 2 month and deficits in number were present at 4 mo. These changes were preceded by decreased availability of insulin, C-peptide and IGF-1 and decreased expression of neurofilaments and beta-III-tubulin. Upregulation of phosphorylating stress kinases like Cdk5, p-GSK-3beta, and p42/44 resulted in increased phosphorylation of neurofilaments. Increasing activity of p-GSK-3beta correlated with increasing phosphorylation of NFH, whereas decreasing Cdk5 correlated with diminishing phosphorylation of NFM. The data suggest that impaired neurotrophic support results in sequentially impaired synthesis and postranslational modifications of neuroskeletal proteins, resulting in progressive deficits in axonal function, maturation and size.
Kamiya
Hideki
H
Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Zhang
Weixian
W
Sima
Anders A F
AA
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D009413:Nerve Fibers, Myelinated / Q000378:metabolism; D009431:Neural Conduction / Q000502:physiology; D010812:Physical Stimulation; D011236:Prediabetic State / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013696:Temperature
D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; C495907:Cdk5 protein, rat; D038362:Glycogen Synthase Kinase 3