title: Gene expressions specifically detected in motor neurons (dynactin 1, early growth response 3, acetyl-CoA transporter, death receptor 5, and cyclin C) differentially correlate to pathologic markers in sporadic amyotrophic lateral sclerosis.
abstract: In a differential gene expression profile, we showed previously that dynactin 1 (DCTN1), early growth response 3 (EGR3), acetyl-CoA transporter (ACATN), death receptor 5 (DR5), and cyclin C (CCNC) were prominently up- or downregulated in motor neurons of sporadic amyotrophic lateral sclerosis (ALS). In the present study, we examined the correlation between the expression levels of these genes and the levels of pathologic markers for motor neuron degeneration (i.e. cytoplasmic accumulation of phosphorylated neurofilament H [pNF-H] and ubiquitylated protein) and the numbers of residual motor neurons in 20 autopsies of patients with sporadic ALS. DCTN1 and EGR3 were widely downregulated, and the changes in gene expression were correlated to the number of residual motor neurons. In particular, DCTN1 was markedly downregulated in most residual motor neurons before the accumulation of pNF-H, even in cases with well-preserved motor neuron populations. ACATN, DR5, and CCNC were upregulated in subpopulations of residual motor neurons, and their expression levels were well correlated with the levels of pNF-H accumulation and the number of residual motor neurons. The expressions of DCTN1, EGR3, ACATN, and DR5 were all markedly altered before ubiquitylated protein accumulation. DCTN1 downregulation appears to be an early event before the appearance of neurodegeneration markers, whereas upregulations of DR5 and CCNC are relatively later phenomena associated with pathologic markers and leading to neuronal death. The sequence of motor neuron-specific gene expression changes in sporadic ALS can be beneficial information in developing appropriate therapeutic strategies for neurodegeneration.
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yue-Mei
authors.initials: YM
authors.lastname: Jiang
authors.forename: Masahiko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ishigaki
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Adachi
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Niwa
authors.forename: Manabu
authors.initials: M
authors.lastname: Doyu
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hashizume
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology* / Q000503:physiopathology*; D056745:Cyclin C; D016213:Cyclins / Q000378:metabolism; D051776:Early Growth Response Protein 3 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism*; D016900:Neurofilament Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D018709:Statistics, Nonparametric; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C503674:CCNC protein, human; D056745:Cyclin C; D016213:Cyclins; C079945:EGR3 protein, human; D026901:Membrane Transport Proteins; D016900:Neurofilament Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D025801:Ubiquitin; C051774:neurofilament protein H; D051776:Early Growth Response Protein 3