Dott. Antonio Piras
- f403-c403 Dottore in Medicina Molecolare
- Dottorato: 24° ciclo
- Matricola: 289045
Tesi di dottorato
AUTOPHAGY ACTIVATION IN NEURODEGENERATIVE DISEASES
Tutor: Alessandro Vercelli
Data discussione tesi: 16/01/2013
Mechanisms of neuronal death in rodent with particular regard to neuroprotection in i) retinal ischemia, ii) amyotrophic lateral sclerosis (ALS) and iii) Spinal muscular atrophy (SMA) mouse model.
Analysis of cortical morphology in particular the structure of dendritic bundles in somatosensory cortex
Attività di ricerca
Abstract
Autophagy is an evolutionarily conserved pathway that involves the sequestration and delivery of cytoplasmic material to the lysosomal degradation. Autophagy plays physiological functions, leading to the degradation of proteins, organelles, toxic agents and supporting mitochondrial turnover. In the last decades, emerging evidence has supported the notion that dysregulation of autophagy might be linked to a growing number of neurodegenerative disorders. The reasons behind autophagic involvement in degenerating neurons can be very diverse: both up- or down regulation can underlie neuronal death.
Despite the authors’ demonstration of its molecular mechanisms and biological functions, it remains unclear whether autophagy acts fundamentally as a cell survival pathway or leads the cell death – or both.
Autophagy may promote cell death through excessive self-digestion and degradation of essential neuron constituents (also known as type II cell death).
Here we present examples of different types of autophagic implications in common neurodegenerative disorders, such as retinal ischemia, spinal muscular atrophy (SMA) and Alzheimer’s disease (AD) and evaluate the relationship with the apoptotic cell death (type I cell death).
Apoptosis and autophagy are both tightly controlled by physiological processes in tissue homeostasis, development and disease.
After retinal ischemia, following increase in intraocular pressure, we have reported up-regulation of autophagy and lysosomal activity. Inhibition of autophagy by 3-methyladenine (3-MA) is followed by a partial prevention of neuron death in the ganglion cell layer.
Considering other approaches, we have found that autophagy is implicated in lower motoneuron (MN) death in a mouse model of SMA pups that have demonstrated up-regulation of autophagy in comparison to the WT in lumbar spinal cord (ventral horn). 3-MA treatment promoted MN survival and maintained motor behaviour performance, suggesting that autophagy could be a novel therapeutic target.
In both models, we have found that apoptosis was strongly linked to the autophagy and inhibition by 3-MA was followed by decrease of type I cell death. After these results we focused our attention to clarify the molecular mechanism that control the switch between two different kinds of cell death: autophagy “self-eating” or apoptosis “self-killing”.
Using a cellular model of Alzheimer’s disease (AD), we have demonstrated that different forms of amyloid beta peptides (Aβ), monomers and oligomers, have triggered respectively autophagy and apoptosis. In our studies, we have found that linkage between Beclin-1, pro-autophagic protein, and Bcl-2, an anti-apoptotic controller, could be an important molecular mechanism for the activation of these different pathways.
Undoubtedly there are multiple connections between the autophagic and apoptotic pathways and the two phenomena jointly lead the fate of the neuron.
The current knowledge on the molecular activation of autophagy is incomplete and fragmented and new studies should yield precious information on its role in various neurodegenerative disease. Autophagy could represent a promising target for treatment in diverse neurodegenerative disorders and it could be very important to understand the time window in which it could be manipulated.
Guglielmotto M., Monteleone D., Boido M., Piras A., Giliberto L., Borghi R., Vercelli A., Fornato M., Tabaton M. and Tamagno E. Aβ1-42-mediated down-regulation of Uch-L1 is dependent on NFκB activation and impaired BACE1 lysosomal degradation. Aging Cell, 2012. DOI: 10.1111/j.1474-9726.2012.00854
Klionsky D.J., Abdalla F.C., Abeliovich H.,[…] Piras A. et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy, 2012. http://dx.doi.org/10.4161/auto.
Piras A., Gianetto D., Conte D., Bosone A. and Vercelli A. Activation of autophagy in a model of retinal ischemia following high intraoclular pressure. PLoS ONE, 2011. PMID: 21799881
Buschini E.*, Piras A.*, Nuzzi R. and Vercelli A. Age related macular degeneration and drusen: neuroinflammation and retina. Progress in Neurobiology, 2011. PMID: 21740956 *equal contribution
Boido M., Buschini E., Piras A., Spigolon G., Valsecchi V., Mazzini L. and Vercelli A. Advantages and pitfalls in experimental models of ALS. Amyotrophic Lateral Sclerosis In-Tech, 2011
Piras A., Schiaffino L., Boido M., Valsecchi V., Guglielmotto M., Tamagno E. and Vercelli A. Autophagy is involved in motoneuron degeneration in a mouse model of SMA. 42nd Annual Meeting Neuroscience – New Orleans, October 13-18, 2012 – Code: 55.15
Boido M., Piras A., Valsecchi V., Spigolon G., Mareski K., Rustichelli D., Mazzini L., Fagioli F. and Vercelli A. Intracisternal delivery of hMSCs in SOD1 mice modulates expression of immunomodulatory molecules and enhances motoneuron survival. 42nd Annual Meeting Neuroscience – New Orleans, October 13-18, 2012
Boido M., D’Errico P., Valsecchi V., Piras A., Locatelli D., Capra S., Colciaghi F., Battaglia G. and Vercelli A. Time course and mechanisms of motoneuron death in a type II spinal muscular atrophy mouse model. 66th National Congress of Italian Society of Anatomy and Istology, 20-23 September 2012, Pistoia (Italy).
Piras A., Boido M., Valsecchi V., Spigolon G., Mareski K., Rustichelli D., Mazzini L., Fagioli F. and Vercelli A. Intracisternal delivery of hMSCs in SOD1 mice modulates expression of immunomodulatory molecules and enhances motoneuron survival. 8th FENS Forum of Neuroscience – International Convention Center – Barcelona - 14-18 July, 2012 - Code: 150.04
Tamagno E., Guglielmotto M., Monteleone D., Boido M., Piras A., Vercelli A. and Tabaton M.Aβ1-42-mediated down-regulation of Uch-L1 is dependent on NF-κB activation and impaired BACE1 lysosomal degradation. 8th FENS Forum of Neuroscience – International Convention Center – Barcelona - 14-18 July, 2012 - Code: 128.18
Piras A., Gianetto D., Conte D. and Vercelli A. Apoptosis and autophagic death in rat ischemic retina. 41th Annual Meeting Neuroscience – Washington, November 12-16, 2011 - 780.25
Boido M., Piras A., Valsecchi V. and Vercelli A. Mechanisms of motoneuron death in a type II spinal muscular atrophy mouse model. 8th IBRO Would Congress of Neuroscience – Florence – July 14-18, 2011 – A487
Piras A., Gianetto D., Conte D., Bosone A. and Vercelli A. Activation of autophagy in a model of retinal ischemia following high intraocular pressure. 8th IBRO Would Congress of Neuroscience – Florence – July 14-18, 2011 – C427
Valsecchi V., Boido M., Spigolon G., Piras A. and Vercelli A. Motorbehavior tests to detect early symptoms in a mouse ALS model. 8th IBRO Would Congress of Neuroscience – Florence – July 14-18, 2011 – D424
Vercelli A., Boido M., Spigolon G., Piras A. and Valsecchi V. Motor behavior tests to detect the early symptoms in a mouse ALS model. 40th Annual Meeting Neuroscience 2010 – San Diego - November 13-17, 2010 – 462.22/T17
Boido M., Toppino D., Piras A., Valsecchi V. and Vercelli A. Mechanisms of motoneuron death in a type II spinal muscular atrophy mouse model. . 40th Annual Meeting Neuroscience 2010 – San Diego, November 13-17, 2010- 864.13/U7
Piras A., Gianetto D., Bosone A. and Vercelli A. Activation of autophagy in a model of retinal ischemia following high intraocular pressure. 7th FENS Forum of European Neuroscience – Rai Center –Amsterdam, July 3-7, 2010
Vercelli A.,Boido M., Toppino D., Piras A., Tonoli E and Valsecchi V. Time-course and modes of motoneuron death in SMA II mice. 7th FENS Forum of European Neuroscience – Rai Center –Amsterdam, July 3-7, 2010
Tonoli E., Piras A., Bosone A. and Vercelli A. Endocytosis and Autophagia in a Rat model of retinal ischemia following high intraocular pressure. National Congress of the Italian Society for Neuroscience - SINS 2009 - Milan Marriott Hotel, october 2-5, 2009
Tonoli E., Piras A., Bosone A. and Vercelli A. Endocytosis and Autophagia in a Rat model of retinal ischemia following high intraocular pressure “ 2nd National Meeting of PhD Students in Neuroscience, New Perspectives in Neuroscience: Research results of Young Italian Neuroscientists. Naple, april 17, 2009
XXII Annual Meeting National Congress of Italian Group of Neuromorpholgy – Bologna – Italy - November 22-23, 2012
42nd Annual Meeting Neuroscience – New Orleans, October 13-18, 2012
41st Annual Meeting Neuroscience – Washington, November 12-16, 2011
8th IBRO Would Congress of Neuroscience – Florence – July 14-18, 2011
XXI Annual Meeting National Congress of Italian Group of Neuromorpholgy - San Benedetto del Tronto (AP) – Italy – June 9-10, 2011
XX Annual Meeting National Congress of Italian Group of Neuromorphology – Turin – Italy – October 22-23, 2010
7th FENS Forum of European Neuroscience – Rai Center -Amsterdam – July 3-7, 2010
Fifth AXREGEN workshop “Nervous System disease and repair: form molecular mechanisms to experience” – Turin – June 29-30, 2010
XIII National Congress of the Italian Society for Neuroscience – SINS 2009 – Milan, October 2-5, 2009
2nd National Meeting of PhD Students in Neuroscience, New Perspectives in Neuroscience: Research results of Young Italian Neuroscieentists. Naples April 17, 2009.
Genes at work on time – Turin, 15-18 October 15-18, 2008
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24-05-12 Silvia Nicolis "Sox2 molecular functions in neural stem cells and the developing brain: insights from conditional mouse mutants”.
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21-09-12 Maurizio Giustetto “ Pathogenensis of Rett syndrome: a neurological childhood disorder”
05-10-12 Cristina Becchio “Grasping the intentions of others: the role of movement kinematics”
09-11-12 Giovanna Gambarotta “The isoforms of ErbB4 receptor and the migration of neuronal progenitors”
16-11-12 Andrea Marcantoni “Early neural impairments in Alzheimer’s disease: moving beyond the hippocampus”
30-12-12 Daniela Rossi “Degenerazione degli astrociti nella Sclerosi Laterale Amiotrofica: meccanismo e protezione farmacologica”
07-12-12 Giovanni Battista Ferrero “La syndrome di Noonan e le RASopatie”