Deregulated expression of cytoskeleton related genes in the spinal cord and sciatic nerve of presymptomatic SOD1G93A Amyotrophic Lateral Sclerosis mouse model

Abstract

Early molecular events related to cytoskeleton are poorly described in Amyotrophic Lateral Sclerosis (ALS), especially in the Schwann cell (SC), which offers strong trophic support to motor neurons. Database for Annotation, Visualization and Integrated Discovery (DAVID) tool identified cytoskeleton-related genes by employing the Cellular Component Ontology (CCO) in a large gene profiling of lumbar spinal cord and sciatic nerve of presymptomatic SOD1G93A mice. One and five CCO terms related to cytoskeleton were described from the spinal cord deregulated genes of 40 days (actin cytoskeleton) and 80 days (microtubule cytoskeleton, cytoskeleton part, actin cytoskeleton, neurofilament cytoskeleton, and cytoskeleton) old transgene mice, respectively. Also, four terms were depicted from the deregulated genes of sciatic nerve of 60 days old transgenes (actin cytoskeleton, cytoskeleton part, microtubule cytoskeleton and cytoskeleton). Kif1b was the unique deregulated gene in more than one studied region or presymptomatic age. The expression of Kif1b [quantitative polymerase chain reaction (qPCR)] elevated in the lumbar spinal cord (40 days old) and decreased in the sciatic nerve (60 days old) of presymptomatic ALS mice, results that were in line to microarray findings. Upregulation (24.8 fold) of Kif1b was seen in laser microdissected enriched immunolabeled motor neurons from the spinal cord of 40 days old presymptomatic SOD1G93A mice. Furthermore, Kif1b was dowregulated in the sciatic nerve Schwann cells of presymptomatic ALS mice (60 days old) that were enriched by means of cell microdissection (6.35 fold), cell sorting (3.53 fold), and primary culture (2.70 fold) technologies. The gene regulation of cytoskeleton molecules is an important occurrence in motor neurons and Schwann cells in presymptomatic stages of ALS and may be relevant in the dying back mechanisms of neuronal death. Furthermore, a differential regulation of Kif1b in the spinal cord and sciatic nerve cells emerged as key event in ALS.

Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis

“…Our finding corroborates the hypothesis that defective monocyte/macrophages infiltration at the site of nerve degeneration may be implicated in ALS. Instead, the network analysis recognized genes belonging to the microtubule cytoskeleton organization, suggesting impairment in axonal transport, in agreement with a previous study analyzing the sciatic nerve of the SOD1 G93A transgenic mice38. Nonetheless, we cannot exclude the possibility that cytoskeleton-related genes dysregulation might reflect a response to injury process rather than having a specific role in disease pathogenesis and neurodegenerative triggering.…”

“…Neuro-inflammation and dysregulated expression of cytoskeleton related genes have been implicated in ALS3738. In ALS motor nerves, our analysis did not reveal any significant over-representation of inflammatory pathways, indirectly supporting the hypothesis that inflammation could be secondary to nerve fibers damage and hence induced in both diseases39.…”

A Case for Microtubule Vulnerability in Amyotrophic Lateral Sclerosis: Altered Dynamics During Disease

“…Kinesin motor proteins transport cell cargo toward the plus end of the MT (anterograde), whereas dynein transport in the minus end direction (retrograde; Maday et al, 2014 ). Kinesin can have an impact on the stability of MTs, and expression of KIF5, a kinesin motor protein isoform, has been found to be decreased in the spinal cord and sciatic nerves of a mutant SOD1 mouse model (Maximino et al, 2014 ). This indicates that altered MT-dependent transport may be depleting MNs via the generation of an energy and signaling deficit.…”

Caracterização do papel da célula de Schwann no processo de neurodegeneração do neurônio motor na esclerose lateral amiotrófica no modelo animal transgênico e no nervo periférico de pacientes: estudo in vitro

“…A expressão gênica no nervo periférico apresenta a minoria dos transcritos relacionados ao axônio e a maioria proveniente das CS (Baraban et al, 2013;Malmqvist et al, 2014;Maximino et al, 2014), fazendo com que a análise molecular do nervo apresente um panorama geral da interação entre CS e NM no contexto da hipótese do dying back na patologia da ELA (Dadon-Nachum et al, 2011;de Oliveira et al, 2014).…”

“…Os procedimentos para a extração do RNA a partir das culturas e do nervo periférico estão descritos em detalhe na nossa publicação (Maximino et al, 2014…”