Boston University Medical Campus
Pathology and Laboratory Medicine

Ivana Delalle. M.D., Ph.D

Assistant Professor

Contact information

Email: idelalle@bu.edu
Tel. 617 414 7014

Education

• Pathology/Neuropathology residency/fellowship, Massachussets General Hospital, Harvard Medical School;
• M.D./ Ph.D, School of Medicine, University of Zagreb, Croatia

Research interests

I. Cytoskeleton and neurodegeneration: This project is aimed at elucidating the relationship between neurodegeneration-associated genetic backgrounds and cytoskeletal rearrangements in neurites of specific neuronal populations in Alzheimer’s disease (AD) and Huntington’s disease (HD) models. Cytoskeletal neuritic abnormalities are neuropathological hallmarks of many neurodegenerative diseases, including AD and HD. However, the mechanisms by which these abnormalities may lead to neurodegeneration remain unclear.  Actin and tubulin are two major cytoskeletal proteins indispensable for normal neurite development and regenerative response upon injury or neurodegenerative stimuli.  Actin capping protein ß2-subunit (Capzb2) is necessary for normal growth cone morphology, neurite length and arborization in hippocampal neurons (Davis et al., 2009).  In addition to regulating microfilament assembly, Capzb2 binds tubulin and, in the presence of microtubule-associated protein tau, affects microtubule polymerization in vitro, a process that is necessary for neurite outgrowth. Accordingly, Capzb2 silencing in hippocampal neurons results in short, poorly branched neurites with abnormal growth cones. This phenotype is reminiscent of morphological changes seen in neurodegeneration, i.e. neuronal processes are reduced in their length and complexity: compare the GFP-labeled mouse hippocampal neuron (green) in which Capzb RNA has been knocked down (below, right) to the control (below, left; blue signal = Capzb).

Interestingly, the levels of Capzb2 protein are increased specifically in the hippocampi of AD patients and in the prefrontal cortices of HD patients.  These data suggest that Capzb2 may play a role in the progression of neurodegeneration associated with AD and HD.

II. miRNAs in schizophrenia and bipolar disorder: This project applies a novel approach towards the search for biological markers for bipolar disorder (BD) and schizophrenia (SCH). Recently, small non-coding RNA molecules (microRNAs, miRNAs) were shown to regulate the expression of human CNS genes involved in cell processes and functions negatively affected in neuropsychiatric disorders, such as synaptic development and maturation, learning and memory.  Exosomes are well-characterized category of secretory vesicles that have been recently shown to contain mRNA, including miRNA.  The interesting property of exosomes is that they are able to attach themselves to recipient cells and release their content including genetic regulatory material such as miRNAs.  Our preliminary data indicate that exosomes can be isolated from frozen postmortem brain tissue (see electron micrograph below).

To test the hypothesis that exosomal miRNA content reflects disease specific-aberrations, we compare exosomal miRNA content in PFCs (Brodmann area 9, BA 9) of patients with BD, SCH and controls to establish BD exosomal miRNA profile. Exosomes are extracted from the frozen postmortem PFCs (BA 9) from the patients diagnosed with SCH, BD and matching controls obtained from Harvard Brain Tissue Resource Center (McLean 66 cohort). To establish cell-type specific miRNA profile in BD we are collaborating with Advanced Tissue Research Center at Harvard NeuroDiscovery Center (Dr. Charles Vanderburg) to use laser capture microscopy (LCM) mapping of neurons and glia in brain regions participating in mood manifestations (BA9, BA24 and ventral striatum) in BD and control samples from McLean 66 cohort. We want to test the hypothesis that major cell- categories in different but interacting brain regions display specifically altered miRNA profiles in BD in comparison to controls. Upon LCM mapping, neuronal and glial miRNAs are obtained using an miRNA extraction kit designed for small amount of miRNA (Molecular Devices Corporation), followed by a sensitive amplification protocol for each of the examined areas. miRNA profiles, both exosomal and cellular are established using liquid phase miRNA multiplex bead arrays (Luminex) and subjected to computational analysis. These experiments aim to improve our understanding of the mechanisms by which the signaling may be altered in BD and SCH. In addition, novel regulatory miRNAs may emerge as potential biological markers for BD and SCH.

Recent Abstracts:

Vanderburg C and Delalle I: Exosomal miRNAs profiles in bipolar disorder and schizophrenia. Keystone Symposium “The Molecular Basis of Schizophrenia and Bipolar Disorder”, Keystone, CO, March 2009.

Selected Articles:

1. Davis DA, Wilson MH, Giraud J, Xie Z, Tseng H-C, England C, Hersckovitz H, Tsai L-H, Delalle I: Capzb2 interacts with ß-tubulin to regulate growth cone morphology and neurite outgrowth (in press at PLoS Biology).
2. Delalle I,  Pfleger CM, Buff E, Lueras P, Hariharan IK. Mutations in the Drosophila orthologs of the F-actin capping protein alpha and beta subunits cause actin accumulation and subsequent retinal degeneration. Genetics 2005; 171:1757-1765.
3. Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai L-H. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. The EMBO Journal 2007; 26/13:3169-79.
4. Kim D, Frank CL, Dobbin MM, Tsunemoto RK, Tu W, Peng PL, Guan JS, Lee BH, Moy LY, Giusti P, Broodie N, Mazitschek R, Delalle I, Haggarty SJ, Neve RL, Lu Y, Tsai L-H: Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron 2008; 60(5): 803-817.