I am a chemist by training and my laboratory has been a cancer biology laboratory for years (see Molecular Cancer Research Cover Art from a recent publication of a graduate student in the laboratory). Traditionally, cancer and neurodegenerative diseases have been considered at the opposite end of the spectrum of human diseases; cancer is characterized by highly dividing cells that resist death while neurodegenerative diseases are associated with death of post-mitotic cells. Today, genetic and cell biology studies show multiple common pathways in cancer and neurodegeneration. This includes pathways that regulate microtubule (MT) stability in cells.
Proper regulation of MT stability is fundamental for neuronal functions and many neurodegenerative diseases are caused or characterized by altered MT dynamics. This is the case of Alzheimer’s disease (AD) and other neurological diseases called tauophathies, where hyperphosphorylation of the MT stabilizing protein Tau, leads to loss of MT mass in the brain.
Mine is among a handful of labs around the world to study a protein called UNC-45A. UNC-45A is a member of UCS domain family highly conserved throughout evolution. Despite its ubiquitousness and conservation, still little is known about its mechanisms of action. We have discovered that UNC-45A, is a key regulator of cytoskeletal functions in mammalian cells, including: a) cytokinesis b) exocytosis in immune cells, and c) axonal growth via regulation of acto-myosin contractility. In addition to UNC-45A’s role in the regulation of acto-myosin system we recently found that UNC-45A is also a novel Microtubule-Associated Protein (MAP) with MT destabilizing activity (see TIRF microscope image of UNC-45 bound to MT).
We are interested in understanding whether and how UNC-45A (see UNC-45A expression in brain) contributes to AD. Our working hypothesis is that UNC-45A is a MT lattice destabilizing protein which is overexpressed in AD and contributes to its initiation and progression. Understanding the molecular mechanisms that regulate neuronal MT mass is significant for targeted therapies for AD.
Because we believe that successful collaborations are at the core of scientific discovery, we have partnered with scientists and researchers across the University, and other national and international institutions. In our investigations we employ the state of the art and cutting-edge reagents and techniques and use clinical specimens of human diseases.
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
- Clemente V, Hoshino A, Meints J, Shetty M, Starr T, Lee M, Bazzaro M. UNC-45A is highly expressed in the proliferative cells of the mouse genital tract and in the microtubule-rich areas of the mouse nervous system. Cells. 2021 Jun 26;10(7):1604.
- Habicht J, Mooneyham A, Hoshino A, Shetty M, Zhang X, Emmings E, Yang Q, Coombes C, Gardner MK, Bazzaro M. UNC-45A breaks the microtubule lattice independently of its effects on non-muscle myosin II. J Cell Sci. 2021 Jan 8;134(1):jcs248815.
- Clemente V, D'Arcy P, Bazzaro M. Deubiquitinating enzymes in coronaviruses and possible therapeutic opportunities for COVID-19. Int J Mol Sci. 2020;21(10):3492. Cover Art.
- Zhang X, Linder S, Bazzaro M. Drug development targeting the ubiquitin-proteasome system (UPS) for the treatment of human cancers. Cancers (Basel). 2020 Apr 7;12(4):902.
- Habicht J, Mooneyham A, Shetty M, Zhang X, Shridhar V, Winterhoff B, Zhang Y, Cepela J, Starr T, Lou E, Bazzaro M. UNC-45A is preferentially expressed in epithelial cells and binds to and co-localizes with interphase MTs. Cancer Biol Ther. 2019;20(10):1304-1313.
- Emmings E, Mullany S, Chang Z, Landen CN Jr, Linder S, Bazzaro M. Targeting mitochondria for treatment of chemoresistant ovarian cancer. Int J Mol Sci. 2019;20(1):229.
- Mooneyham A, Iizuka Y, Yang Q, Coombes C, McClellan M, Shridhar V, Emmings E, Shetty M, Chen L, Ai T, Meints J, Lee MK, Gardner M, Bazzaro M. UNC-45A is a novel microtubule-associated protein and regulator of paclitaxel sensitivity in ovarian cancer cells. Mol Cancer Res. 2019;17(2):370-383. Cover Art.
- Hellweg R, Mooneyham A, Chang Z, Shetty M, Emmings E, Iizuka Y, Clark C, Starr T, Abrahante JH, Schütz F, Konecny G, Argenta P, Bazzaro M. RNA sequencing of carboplatin- and paclitaxel-resistant endometrial cancer cells reveals new stratification markers and molecular targets for cancer treatment. Horm Cancer. 2018;9(5):326-337. Cover Art
- Iizuka Y, Mooneyham A, Sieben A, Chen K, Maile M, Hellweg R, Schütz F, Teckle K, Starr T, Thayanithy V, Vogel RI, Lou E, Lee MK, Bazzaro M. UNC-45A is required for neurite extension via controlling NMII activation. Mol Biol Cell. 2017;28(10):1337-1346.
- Vogel RI, Pulver T, Heilmann W, Mooneyham A, Mullany S, Zhao X, Shahi M, Richter J, Klein M, Chen L, Ding R, Konecny G, Kommoss S, Winterhoff B, Ghebre R, Bazzaro M. USP14 is a predictor of recurrence in endometrial cancer and a molecular target for endometrial cancer treatment. Oncotarget. 2016 May 24;7(21):30962-76.
- Iizuka Y, Cichocki F, Sieben A, Sforza F, Karim R, Coughlin K, Isaksson Vogel R, Gavioli R, McCullar V, Lenvik T, Lee M, Miller J, Bazzaro M. UNC-45A is a nonmuscle myosin IIA chaperone required for NK cell cytotoxicity via control of lytic granule secretion. Immunol. 2015 Nov 15;195(10):4760-70.
- Coughlin K, Anchoori R, Iizuka Y, Meints J, MacNeill L, Vogel RI, Orlowski RZ, Lee MK, Roden RB, Bazzaro M. Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses. Clin Cancer Res. 2014;20(12):3174-86.