Gene expression analysis of frontotemporal lobar degeneration of the motor neuron disease type with ubiquitinated inclusions.
Neurodegenerative disorders share a process of aggregation of insoluble protein. Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) is characterized by the presence of ubiquitin and TDP-43 positive aggregates which are likely related to specific gene expression profiles. We carried out gene expression microarray analysis on post-mortem brain tissue from FTLD-U, FTLD-MND, and controls. Using total RNA from carefully dissected frontal cortical layer II, we obtained gene expression profiles showing that FTLD-U and controls differ in over 100 networks, including those involved in synapse formation, the ubiquitin-proteasome system, endosomal sorting, and apoptosis. We performed qRT-PCR validation for three genes, representative of three different networks. Dynein axonemal light intermediate chain 1 (DNALI1) (microtubule/cytoskeleton network associated) expression was 3-fold higher and myeloid differentiation primary response gene 88 (MYD88) (signal transduction network) was 3.3 times higher in FTLD-U than FTLD-MND and controls; annexin A2 (ANXA2) (endosomal sorting) expression was 11.3-fold higher in FTLD-U than FTLD-MND and 2.3-fold higher than controls. The identification of progranulin (PGRN) gene mutations and TDP-43 as the major protein component of the ubiquitinated inclusions, are two recent landmark discoveries in the field of FTLD-U. We found 1.5-fold increase in TDP-43 in both FTLD-MND and FTLD-U while progranulin showed no gene expression differences between controls and FTLD-MND. However, one of the FTLD-U cases tested by Affymetrix microarray showed "absence call" of this transcript, suggesting absent or decreased gene expression. Our findings point to specific gene-linked-pathways which may be influenced by neurodegenerative disease process and may be targeted for further exploration.
Mishra
Manjari
M
Cognitive Neurology and Alzheimer Disease Center, Northwestern University, Feinberg School of Medicine, 320 East Superior St, Chicago, IL, 60611, USA. manjari@northwestern.edu
Paunesku
Tatjana
T
Woloschak
Gayle E
GE
Siddique
Teepu
T
Zhu
Lihua Julie
LJ
Lin
Simon
S
Greco
Kristin
K
Bigio
Eileen H
EH
D000368:Aged; D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism; D056444:Axonemal Dyneins; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003704:Dementia / Q000378:metabolism* / Q000473:pathology; D004398:Dyneins / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000378:metabolism* / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D000077153:Progranulins; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
D017306:Annexin A2; D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D000077153:Progranulins; D025801:Ubiquitin; D056444:Axonemal Dyneins; C430745:DNAH9 protein, human; D004398:Dyneins