Proteomic analysis in giant axonal neuropathy: New insights into disease mechanisms

Abstract

Several of the dysregulated proteins play a role in cytoskeletal reorganization. Based on these findings, we speculate that disturbed cytoskeletal regulation is responsible for formation of aggregates of intermediate filaments.

Intermediate Filaments in Neurodegenerative Diseases

“…These results indicated that the generalized disorganization of IFs in GAN patients may not involve TBCB-mediated MT disassembly and must be regulated by a yet unidentified mechanism [106]. Recently, proteomic analysis performed in fibroblasts from four GAN patients provided new insights into disease mechanisms [124]. Although the major role of gigaxonin is reported to be degradation of cytoskeleton-associated proteins, the amount of 76 structural cytoskeletal proteins was unaltered.…”

“…In the case of fibroblasts, disturbed cytoskeletal regulation could lead to a hyperphosphorylation state of vimentin that results in massive depolymerization of vimentin filaments and finally in collapse of the vimentin network. The unpolymerized filaments are collected in the aggresome near the nucleus where they form the typical aggregates [124].…”

Restoration of Cytoskeleton Homeostasis After Gigaxonin Gene Transfer for Giant Axonal Neuropathy

“…· 150 mm length · 5 lm, 100 Å column; Phenomenex), as described by Mussche et al (2012). The buffer compositions were 20 mM HCOONH 4 , 2% ACN at pH 10 for buffer A and 20 mM HCOONH 4 , 80% ACN at pH 10 for buffer B.…”

“…Off-line LC-MS was done as described by Mussche et al (2012). Briefly, analytical reversed phase separation of the labeled peptide mixture was performed on an Ultimate Plus Dual-gradient Capillary/Nano-LC system (Dionex-LC Packings) using a C18 column (75 lm i.d.…”

“…Galectin-1 and DJ-1 were selected, as according to the iTRAQ results these were significantly down-regulated following gigaxonin gene transfer, and galectin-1 was previously shown to be overexpressed in GAN patients compared to controls (Mussche et al, 2012). This means that this is probably an important player in GAN.…”