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

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Abstract

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.

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Acknowledgments

We are grateful to the patients and their families who generously donated their brains for research. This work was supported in part by NIH grants AG13854 (MM and EHB), and grants CA81375-03, CA81375-03S1 to TP and GEW.

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Authors and Affiliations

  1. Cognitive Neurology and Alzheimer Disease Center, Northwestern University, Feinberg School of Medicine, 320 East Superior St, Chicago, IL, 60611, USA

    Manjari Mishra, Kristin Greco & Eileen H. Bigio

  2. Department of Radiation Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA

    Tatjana Paunesku & Gayle E. Woloschak

  3. Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA

    Teepu Siddique

  4. Department of Bioinformatics Core, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA

    Lihua (Julie) Zhu & Simon Lin

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  1. Manjari Mishra
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Mishra, M., Paunesku, T., Woloschak, G.E. et al. Gene expression analysis of frontotemporal lobar degeneration of the motor neuron disease type with ubiquitinated inclusions. Acta Neuropathol 114, 81–94 (2007). https://doi.org/10.1007/s00401-007-0240-7

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