Laboratory of Applied Biology
Prof. Angelo Poletti
Mariarita Galbiati, Assistant Professor
Paola Rusmini, Assistant Professor
Valeria Crippa, Post doc research fellow
Maria Elena Cicardi, Post doc student
Riccardo Cristofani, Post doc student
Marco Meroni, Post doc student
Margherita Piccolella, Technician
Our laboratory is involved in two main projects:
1) the study of the molecular mechanisms at the basis of two different motor neuron diseases (MNDs): the Amyotrophic Lateral Sclerosis (ALS) and the SpinoBulbar Muscular Atrophy (SBMA).
2) the role of androgenic derivatives with estrogenic activity in prostate cancer.
Line 1) With regards to the two forms of MNDs (ALS and SBMA) these are associated to the formation of aberrant mutant protein conformations (misfolded species) that, because of this, become neurotoxic. These neurotoxic misfolded species may aggregate inside the motoneurons and/or perturb several basis mechanisms controlling neuronal functions leading to death. It is thus fundamental to prevent protein misfolding to counteract motoneuronal loss in MNDs. We recently identified a protective effect of a small heat shock protein (HSPB8) in the two diseases. HSPB8 has a potent pro-degradative, anti-aggregant activity on the mutant misfolded species of proteins responsible for MNDs. His action seems to be mediated by the activation of autophagy and can be potentiated by other pharmacologic inducers of the autophagic process suggesting novel potential therapeutic approaches for these fatal disorders.
Line 2) In the project on prostate cancer, we have recently proved a potent antiproliferative, antimetastatic activity of an androgen metabolite, the 3beta-diol. This compound is physiologically locally produced from testosterone in prostate cells, where it may counterbalance the pro-proliferative activity of its androgenic precursor. 3beta-diol has been considered for a long time an inactive compound since it is devoid of androgenic activity. We found that 3beta-diol has a potent estrogenic activity and can be considered one of the physiological estrogenic compound in male. We demonstrated that 3beta-diol exerts its potent anti-cancer effects by the selective activation of the estrogen receptor beta, which is expressed in prostate cancer cells, and induces the production of the anti-metastatic protein E-cadherin. We are now searching for synthetic and natural analogs of 3beta-diol that can be tested to be used in the future treatment of prostate cancer.
1. Motoneuronal cell death is not correlated with aggregate formation of androgen receptors containing an elongated polyglutamine tract.
Simeoni S., Mancini M.A., Stenoien D., Marcelli M., Weigel N.L., Zanisi M., Martini L., Poletti A.
Hum Mol Genet (2000) 9:133-144.
2. The Androgen Derivative 5alpha-Androstan-3beta,17beta-diol Inhibits Prostate Cancer Cell Migration throught Activation of Estrogen Receptor beta subtype.
Guerini V., Sau D., Scaccianoce E., Rusmini P., Ciana P., Maggi A., Martini P.G., Katznenellenbogen B.S., Martini L., Motta M., Poletti A.
Cancer Res (2005) 65:5445-5453
3. Aggregation and Proteasome: The case of elongated polyglutamine aggregation in Spinal and Bulbar Muscular Atrophy.
Rusmini P., Sau D., Crippa V., Palazzolo I., Simonini F., Onesto E., Martini L., Poletti A.
Neurobiol Aging (2007) 28:1099-1111
4. Mutation of the SOD1 in ALS: a Gain of a Loss of function.
Sau D., De Biasi S., Vitellaro-Zuccarello L., Riso P, Guarnieri S, Porrini M, Simeoni S., Crippa V., Onesto E., Palazzolo I., Rusmini P., Bolzoni E., Bendotti C., Poletti A.
Hum Mol Genet (2007) 16:1604-1618
5. The Small Heat Shock Protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in Amyotrophic Lateral Sclerosis (ALS).
Crippa V., Sau D., Rusmini P., Boncoraglio A., Onesto E., Bolzoni E., Galbiati M., Fontana E., Marino M., Carra S., Bendotti C., De Biasi S., Poletti A.
Hum Mol Genet (2010) 19:3440-3456.
6. Estrogen receptor β and the progression of prostate cancer: role of 5a-androstane-3β,17β-diol (3β-Adiol).
Dondi D., Piccolella M., Biserni A., Della Torre S., Ramachandran B., Locatelli A., Rusmini P., Sau D., Maggi A., Ciana P., Poletti A.
Endocr-Relat Cancer (2010) 17:731-742.
7. Muscle cells and Motorneurons Differentially Remove Mutant SOD1 Causing Familial Amyotrophic Lateral Sclerosis.
Onesto E., Rusmini P., Crippa V., Ferri N., Zito A., Galbiati R., Poletti A.
J Neurochem (2011) 118:266-280
8. The anabolic/androgenic steroid Nandrolone exacerbates gene expression modifications induced by mutant SOD1 in muscles of mice models of amyotrophic lateral sclerosis.
Galbiati M., Onesto E., Zito A., Crippa V., Rusmini P., Mariotti R., Bentivoglio B., Bendotti C., Poletti A.
Pharmacol. Res. (2012) 65:221-230.
9. Neuritin 1 promotes migration of immortalized neurons modulating microtubule stability
Zito A., Cartelli D., Cappelletti G., Cariboni A., Poletti A., Galbiati M.
Brain Structure and Function (2013) (in press)
10. Clearance of the mutant AR in motoneuronal models of Spinal and Bulbar Muscular Atrophy
Rusmini P., Crippa V., Giorgetti E., Boncoraglio A., Cristofani R., Carra S., Poletti A.
Neurobiol Aging (2013) in press.