“Cell Therapy: An Emerging Drug Class” Biju Parekkadan, PhD Assistant Professor of Surgery Harvard Medical...
Ivana Delalle. M.D., Ph.D
Tel. 617 414 7014
- Pathology/Neuropathology residency/fellowship, Massachussets General Hospital, Harvard Medical School;
- M.D./ Ph.D, School of Medicine, University of Zagreb, Croatia
Exosomal microRNA (miRNA, miR) as a biomarker in neuropsychiatric diseases
We recently successfully hypothesized that exosomal miRNA expression in brains of patients diagnosed with schizophrenia (SZ) and bipolar disorder (BD) might differ from controls, reflecting either disease-specific or common aberrations in SZ and BD patients. The sources of the analyzed samples included McLean 66 Cohort Collection (Harvard Brain Tissue Resource Center), BrainNet Europe II (BNE, a consortium of 18 brain banks across Europe) and Boston Medical Center (BMC). Exosomal miRNAs from frozen postmortem prefrontal cortices with well-preserved RNA were isolated and submitted to profiling by Luminex FLEXMAP 3D microfluidic device at Harvard NeuroDiscovery Center. Multiple statistical analyses of microarray data suggested that certain exosomal miRNAs were differentially expressed in prefrontal cortices (Brodmann area 9, BA9) of SZ and BD subjects in comparison to controls. RT-PCR validation confirmed that two miRNAs, miR-497 in SZ samples and miR-29c in BD samples, have significantly increased expression when compared to control samples (Banigan, Kao et al., PLoS One 2013).
Bipolar Disorder (BD) is a costly, common, and highly polygenic disease with
marked clinical heterogeneity and overlap with other mental diseases. Early identification
of individuals who will become BD or major depressive disorder (MDD) patients with
bipolar features may contribute to better treatment and prognosis. However, BD
biomarkers do not exist in clinical practice. Our above-mentioned study of exosomal miR expression in prefrontal cortex in BD patients and controls yielded miR-29c as a putative BD exosomal miR biomarker. The results of an ongoing analysis of exosomal miRNAs in CSF samples of BD patients and controls are in agreement. These data prompt us to, together with our colleagues in Goettingen University (PI: Professor Andre Fischer) employ Next Generation Sequencing (NGS, RNA Seq), a method with higher sensitivity, to find exosomal miRNA biomarker candidates in CSF and/or plasma samples that may distinguish BD patients from healthy individuals. The samples available for this study are being collected also under international Consortium on Lithium Genetics (PI: Professor Thomas Schulze, Goettingen University), the largest consortium ever to study the genetic underpinnings of response to lithium treatment in BD (www.ConLiGen.org). Because of the clinical and neuropathological overlap of BD and MDD, samples from MDD patients will be examined as well.
Importantly for the reported reduction of BA24 glial cell numbers in BD and MDD, the miRNAs that apparently have differential expression in BD BA24 samples in comparison to controls according to our analysis, have been also implicated in glial proliferation and cell differentiation/death. In addition, we have observed differential expression of these miRNAs in whole brain exosomes of a well-validated animal depression model that features dysfunctional hippocampal astrocytes, flinders sensitive line (FSL) rat strain. In FSL rats, dysfunctional hippocampal astrocytes underlie depression- associated memory impairment. Together, our studies support the notion the exosomal miRNAs may have a potential to not only serve as BD biomarkers but could also provide the link between BD neuropathology and its pathogenesis, thereby guiding future therapeutic interventions.
- Banigan MG, Kao PF (co-first author), Kozubek JA, Winslow AR, Medina J, Costa J, Schmitt A, Schneider A, Cabral H, Cagsal-Getkin O, Vanderburg CR, and Delalle I: Differential expression of exosomal miRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients. PLoS One 2013; 8(1):e48814.doi:10.1371/journal.pone.0048814.
- Kao PF, Banigan MG, Vanderburg CR, McKee AC, Polgar P, Seshadri S, and Delalle I: Increased expression of TrkB and Capzb2 accompanies preserved cognitive status in early Alzheimer’s disease pathology. J. Neuropathology Exp. Neurology 2012; 71(7):654-664.
- Graeff J, Guan J-S, Rei D, Wang W-Y, Hennig KM, Nieland TJF, Fass DJ, Kao PF, Kahn M, Joseph N, Haggarty SJ, Delalle I, and Tsai L-H: An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 2012; 483:222-226.
- Bahri-Javan S, Maddalena A, Kerimoglu C, Wittnam J, Held T, Bahr M, Burkhardt S, Delalle I, Kugler S, Fischer A, and Sananbenesi F. HDAC1 regulates fear extinction in mice. J Neuroscience 2012; 32(15): 5062-73.
- Zovoilis A, Agbemenyah HY, Agis-Balboa RC, Stilling RM , Rao P , Edbauer D, Farinelli L, Delalle I , Schmitt A, Falkai P, Bahari-Javan, S Burkhardt S , Sananbenesi F, and Fischer A: microRNA-34c is a novel target to treat dementias. The EMBO J 2011; 30(20):4299-308.
- Kao PF, Davis DA, Banigan MG, Vanderburg CR, Seshadri S, and Delalle I: Modulators of cytoskeletal reorganization in CA1 hippocampal neurons show increased expression in patients at mid-stage Alzheimer’s disease. PLoS One 2010 Oct 13;5(10):e13337.
- Davis DA, Wilson MH, Giraud J, Xie Z, Tseng H-C, England C, Hersckovitz H, Tsai L-H, and Delalle I: Capzb2 interacts with ß-tubulin to regulate growth cone morphology and neurite outgrowth. PLoS Biol 7(10) 2009; e1000208. doi:10.1371/journal.pbio.1000208.