Combined Transcriptomics and Proteomics in Frontal Cortex Area 8 in Frontotemporal Lobar Degeneration Linked to C9ORF72 Expansion

Article type: Research Article

Authors: Andrés-Benito, Pol^{a; b} | Gelpi, Ellen^{c; d} | Povedano, Mónica^g | Ausín, Karina^{h; i} | Fernández-Irigoyen, Joaquín^{h; i} | Santamaría, Enrique^{h; i} | Ferrer, Isidro^{a; b; e; f; *}

Affiliations: [a] Neuropathology, Pathologic Anatomy Service, Bellvitge University Hospital - Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Spain | [b] Biomedical Network Research Center on Neurodegenerative Diseases (CIBERNED), Institute of Health Carlos III, Hospitalet de Llobregat, Spain | [c] Neurological Tissue Bank of the Biobanc-Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain | [d] Institute of Neurology, Medical University of Vienna, Vienna, Austria | [e] Department of Pathology and Experimental Therapeutics, University of Barcelona, Hospitalet de Llobregat, Spain | [f] Institute of Neurosciences, University of Barcelona, Barcelona, Spain | [g] Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain | [h] IDISNA, Navarra Institute for Health Research, Pamplona, Spain | [i] Clinical Neuroproteomics group and Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Department of Health, Public University of Navarra, Pamplona, Spain

Correspondence: [*] Correspondence to: Prof. Isidro Ferrer, Department of Pathology and Experimental Therapeutics, University of Barcelona, Campus Bellvitge, c/Feixa Llarga sn, 08907 L’Hospitalet de Llobregat, Spain. Tel.: +34 93 4035808; E-mail: [email protected].

Abstract: Background:Frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) may appear as sporadic (sFTLD-TDP) or linked to mutations in various genes including expansions of the non-coding region of C9ORF72 (c9FTLD). Objective:Analysis of differential mRNA and protein expression in the frontal cortex in c9FLTD and evaluation with previous observations in frontal cortex in sFTLD-TDP and amyotrophic lateral sclerosis with TDP-43 inclusions. Methods:Microarray hybridization and mass spectrometry-based quantitative proteomics followed by RT-qPCR, gel electrophoresis, and western blotting in frontal cortex area 8 in 19 c9FTLD cases and 14 age- and gender-matched controls. Results:Microarray hybridization distinguish altered gene transcription related to DNA recombination, RNA splicing regulation, RNA polymerase transcription, myelin synthesis, calcium regulation, and ubiquitin-proteasome system in c9FTLD; proteomics performed in the same tissue samples pinpoints abnormal protein expression involving apoptosis, inflammation, metabolism of amino acids, metabolism of carbohydrates, metabolism of membrane lipid derivatives, microtubule dynamics, morphology of mitochondria, neuritogenesis, neurotransmission, phagocytosis, receptor-mediated endocytosis, synthesis of reactive oxygen species, and calcium signaling in c9FTLD. Conclusion:Transcriptomics and proteomics, as well as bioinformatics processing of derived data, reveal similarly altered pathways in the frontal cortex in c9FTLD, but different RNAs and proteins are identified by these methods. Combined non-targeted ‘-omics’ is a valuable approach to deciphering altered molecular pathways in FTLD provided that observations are approached with caution when assessing human postmortem brain samples.

Keywords: C9ORF72, frontotemporal lobar degeneration, FTLD-TDP, gene expression, proteomics

DOI: 10.3233/JAD-181123

Journal: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1287-1307, 2019