What is the impact of androgens on age-related diseases, such as prostate cancer and neurodegeneration?

How does the amplification of androgen receptor function alter gene expression ultimately triggering cancer and neurodegeneration?

Cancer and neurodegenerative diseases represent a major health burden for the world. Aging is the major risk factor for these untreatable diseases. We are interested in understanding i) What is the relationship between protein context (structure and function) and neurotoxicity/cancer; ii) How specific extra- and intra-cellular signaling pathways directly target the disease-related protein through post-translational modifications that suppress and enhance toxicity; iii) How single-cell molecular identity shapes selective neuronal vulnerability; and iv) What is the role of peripheral tissues in the neurodegenerative process.

Androgen receptor (AR) belongs to the family of nuclear hormone receptors, which also includes oestrogen, glucocorticoid, progesterone, and mineralocorticoid receptors. In its inactive state, AR resides in the cytosol in association with heat shock proteins (HSPs). Upon binding to its natural ligands, testosterone (T) and the more potent derivative dihydrotestosterone (DHT), AR dissociates from HSPs, dimerizes and translocates to nucleus, where it binds to specific sequences on the DNA known as androgen-responsive elements (ARE). Upon interaction with transcription co-factors (co-activators and co-repressors) and the basal transcription complex machinery, AR regulates the expression of the androgen-responsive genes. In addition, AR undergoes several post-translational modifications (PTMs), such as phosphorylation, methylation, acetylation and ubiquitination. AR is a ubiquitous protein. Partial or complete AR loss-of-function (LOF) mutations lead to different degrees of androgen insensitivity syndrome, whereas gain-of-function (GOF) mutations result in two clinically distinct age-related diseases, prostate cancer (PC) and spinobulbar muscular atrophy (SBMA).

We have previously established that i) Androgen-induced AR nuclear translocation, DNA binding and interaction with transcription co-factors are all necessary steps towards neurodegeneration in SBMA; ii) Signaling pathways culminating in direct modification of AR affect its response to androgens, thereby resulting in major changes in protein structure, function, and toxicity; and iii) Peripheral tissues, such as skeletal muscle, play a key role in SBMA, indicating that AR expression in these tissues is important for disease pathogenesis. These findings imply that the toxic GOF underlying SBMA involves modification of the native function of AR, suggesting converging mechanisms with PC. Moreover, the observation that PTMs of AR affect its structure-folding, native function and toxicity offers the opportunity to identify agents that enhance PTMs suppressing toxicity and test these compounds for therapeutic purposes. Based on our results obtained in mice, two agents have been moved to phase II clinical trials for SBMA. We are currently exploring the molecular details of AR dysfunction and deregulation of androgen-responsive gene expression. Moreover, we are investigating what is the role of AR in peripheral tissues in health and disease.  

Maria Pennuto

  • PhD: University of Milan, Italy (2000)
  • Post-doc San Raffaele Scientific Institute, Milan, Italy (2001-2004)
  • Post-doc NINDS, NIH, Bethesda MD, USA (2005-2007)
  • Staff Scientist University of Pennsylvania, Philadelphia PA, USA (2008-2009)
  • Group Leader Italian Institute of Technology Genoa, Italy (2009-2013)
  • Professor: Assistant & Associate Professor, University of Trento, Italy (2013-2017)
  • Professor: Associate Professor of Molecular Biology, University of Padua, Italy (2017-current)
  • Group leader: Veneto Institute of Molecular Medicine, Padua, Italy (2018-current)

Selected Awards

  • 2017  Arimura Foundation State-of-Art Lecture Award, 13th International PACAP meeting, Hong Kong
  • 2013  Dulbecco Telethon Institute Career Award
  • 2011  IBRO selected Lecture “Woman in Neuroscience”, 10th International PACAP meeting, Israel
  • 2003  Euresco Travel Award
  • 1998  European Science Foundation Travel Award
  • 1997  A. Marzullo National Award for Undergraduate Thesis, University of Trieste, Italy