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. Our preliminary studies show that actin capping protein ß2-subunit (Capzb2) is necessary for normal growth cone morphology, neurite length and arborization in hippocampal neurons. 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 protein).

Interestingly, the levels of Capzb2 protein are altered in the hippocampi of AD patients and in the heads of caudate nuclei and prefrontal cortices of HD patients. These data suggest that Capzb2 may play a role in the neurodegeneration associated with AD and HD. We want to test the hypothesis that Capzb2 may support the regenerative response of neurons following degenerative stimuli by coordinating the rearrangement of the actin and microtubule cytoskeleton in the growth cone. Firstly, we want to determine how changing levels of Capzb2 may modify morphology of neurites and/or neuronal survival in aged AD and HD transgenic mice in vivo. Secondly, we want to establish how mutations associated with AD or HD modulate the effects of Capzb2 on neurite outgrowth, growth cone morphology, and microtubule polymerization in cultured neurons. These experiments should improve our understanding of the mechanisms by which AD- and HD-associated genetic backgrounds influence neurite morphology and lead to cytoskeletal abnormalities that may contribute to neuronal demise.

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:

  1. Vanderburg C, Delalle I: Exosomal miRNAs profiles in bipolar disorder and schizophrenia. Keystone Symposia, Keystone, CO, March 2009.
  2. Wilson MH, Giraud J, Xie Z, Tseng H-C, Tsai L-H, Delalle I. F-actin capping protein beta2-subunit (Capzb2) binds tubulin and affects tubulin polymerization in vitro. Society for Neuroscience Meeting, San Diego, CA, November 2007
  3. Davis DA, Diamond RE, Vanderburg C, Delalle I. F-actin capping protein beta subunit brain isoform (Capzb2) mRNA and protein expression in Alzheimer’s Disease (AD) and Huntington’s disease (HD). Society for Neuroscience Meeting, San Diego, CA, November 2007.

Selected Articles:

  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, 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
  4. 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.
  5. Brouns MR, Matheson SF, Hu K-Q, Delalle I, Caviness VS Jr, Silver J, Bronson RT, Settleman J.The adhesion signaling molecule p190 RhoGAP is required for morphogenetic processes in neural development. Development 2000;127:4891-4903.
  6. Delalle I, Takahashi T, Nowakowski RS, Tsai L-H and Caviness VS Jr. Cyclin E – p27 opposition and regulation of the G1 phase of the cell cycle in the murine neocortical PVE: a quantitative analysis of mRNA in situ hybridization. Cerebral Cortex 1999;9/8:824-832.
  7. Tsai L-H, Delalle I, Caviness VS Jr, Chae T and Harlow E. p35, a neural specific regulatory subunit of the cdk5 kinase. Nature 1994;371:419-423.
Primary teaching affiliate
of BU School of Medicine