TY - JOUR
T1 - Microarray analysis of the cellular pathways involved in the adaptation to and progression of motor neuron injury in the SOD1 G93A mouse model of familial ALS.
AU - Ferraiuolo, Laura
AU - Heath, Paul R
AU - Holden, Hazel
AU - Kasher, Paul
AU - Kirby, Janine
AU - Shaw, Pamela J
N1 - , Wellcome Trust, United Kingdom
PY - 2007/8/22
Y1 - 2007/8/22
N2 - The cellular pathways of motor neuronal injury have been investigated in the SOD1 G93A murine model of familial amyotrophic lateral sclerosis (ALS) using laser-capture microdissection and microarray analysis. The advantages of this study include the following: analysis of changes specifically in motor neurons (MNs), while still detecting effects of interactions with neighboring cells; the ability to profile changes during disease progression, an approach not possible in human ALS; and the use of transgenic mice bred on a homogeneous genetic background, eliminating the confounding effects arising from a mixed genetic background. By using this rigorous approach, novel changes in key cellular pathways have been detected at both the presymptomatic and late stages, which have been validated by quantitative reverse transcription-PCR. At the presymptomatic stage (60 d), MNs extracted from SOD1 G93A mice show a significant increase in expression of genes subserving both transcriptional and translational functions, as well as lipid and carbohydrate metabolism, mitochondrial preprotein translocation, and respiratory chain function, suggesting activation of a strong cellular adaptive response. Mice 90 d old still show upregulation of genes involved in carbohydrate metabolism, whereas transcription and mRNA processing genes begin to show downregulation. Late in the disease course (120 d), important findings include the following: marked transcriptional repression, with downregulation of multiple transcripts involved in transcriptional and metabolic functions; upregulation of complement system components; and increased expression of key cyclins involved in cell-cycle regulation. The changes described in the motor neuron transcriptome evolving during the disease course highlight potential novel targets for neuroprotective therapeutic intervention.
AB - The cellular pathways of motor neuronal injury have been investigated in the SOD1 G93A murine model of familial amyotrophic lateral sclerosis (ALS) using laser-capture microdissection and microarray analysis. The advantages of this study include the following: analysis of changes specifically in motor neurons (MNs), while still detecting effects of interactions with neighboring cells; the ability to profile changes during disease progression, an approach not possible in human ALS; and the use of transgenic mice bred on a homogeneous genetic background, eliminating the confounding effects arising from a mixed genetic background. By using this rigorous approach, novel changes in key cellular pathways have been detected at both the presymptomatic and late stages, which have been validated by quantitative reverse transcription-PCR. At the presymptomatic stage (60 d), MNs extracted from SOD1 G93A mice show a significant increase in expression of genes subserving both transcriptional and translational functions, as well as lipid and carbohydrate metabolism, mitochondrial preprotein translocation, and respiratory chain function, suggesting activation of a strong cellular adaptive response. Mice 90 d old still show upregulation of genes involved in carbohydrate metabolism, whereas transcription and mRNA processing genes begin to show downregulation. Late in the disease course (120 d), important findings include the following: marked transcriptional repression, with downregulation of multiple transcripts involved in transcriptional and metabolic functions; upregulation of complement system components; and increased expression of key cyclins involved in cell-cycle regulation. The changes described in the motor neuron transcriptome evolving during the disease course highlight potential novel targets for neuroprotective therapeutic intervention.
U2 - 10.1523/JNEUROSCI.1470-07.2007
DO - 10.1523/JNEUROSCI.1470-07.2007
M3 - Article
C2 - 17715356
SN - 1529-2401
VL - 27
JO - The Journal of neuroscience : the official journal of the Society for Neuroscience
JF - The Journal of neuroscience : the official journal of the Society for Neuroscience
IS - 34
ER -