Gene expression analysis of frontotemporal lobar degeneration of the motor neuron disease type with ubiquitinated inclusions

• DOI: 10.1007/s00401-007-0240-7
• Publication Date: 2007-06-14T06:29:31Z
• Authors: Manjari Mishra; Tatjana Paunesku; Gayle E. Woloschak; Teepu Siddique; Lihua Zhu; Simon Lin; Kristin Greco; Eileen H. Bigio
• Keywords: Inclusion Bodies; Male; Ubiquitin; Gene Expression Profiling; Dyneins; Axonemal Dyneins; Middle Aged; DNA-Binding Proteins; 03 medical and health sciences; Progranulins; 0302 clinical medicine; Gene Expression Regulation; Case-Control Studies; Myeloid Differentiation Factor 88; Humans; Intercellular Signaling Peptides and Proteins; Dementia; Female; Motor Neuron Disease; Annexin A2; Aged; Oligonucleotide Array Sequence Analysis

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.