Our laboratory studies the molecular changes underlying the neuronal network associated with neurodegenerative diseases, including Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis (ALS).

 

The two main topics of our research are the study of SUMOylation, a post-translational protein modification that regulates the localization, expression, degradation and protein aggregation, and the analysis of neurotransmitter release mechanisms.

 

Our running projects are:

 

1. Role of SUMO and TDP43 interaction in ALS

 

The aim of the research is to characterize the SUMOylation of TDP-43 (transactive response DNA binding protein 43 kDa), an altered protein in patients affected by ALS. Our focus is to study the SUMO and TDP43 crosstalk, evaluating how SUMOylation influences the cell localization, biological activity, nucleus / cytosol transport and pathological aggregation of TDP43 in ALS. The project tends to understand the physio-pathological role of SUMO and TDP43 interaction in ALS in order to identify it as possible therapeutic targets to tackle this pathology.

 

2. Role of SUMO and Tau protein interaction in AD

 

Besides several activities, SUMOylation also regulates synaptic transmission and plasticity which are altered in various neurological pathologies including AD disease. In fact, SUMO has been shown to bind covalently the precursor of the β-amyloid protein (APP) and Tau, key proteins in neurodegenerative processes. The aim of the research is to study the SUMO / Tau interaction both in mouse models affected by AD and on biological samples / autoptic tissues of AD patients, to understand the mechanisms underlying this crosstalk. This knowledge would give the opportunity to identify new therapeutic targets to develop new drug therapies for this pathology.

 

3. Development of SUMO inhibitor cell-permeable peptides

 

The purpose of this research line is to design and test, both in vitro and in vivo, specific cell-permeable peptides capable of reducing / increasing protein SUMOylation with the aim of studying whether an alteration of the SUMO / deSUMOylation balance can modify the activity, the aggregation and the expression of key mediators of neurodegenerative processes in both AD and ALS.

 

4. Study of the presynaptic role of JNK.

 

Activation of the c-Jun N-terminal kinase (JNK) protein is a critical step for neuronal death occurring in various neurological pathologies. JNKs are activated by various stress-causing stimuli and receptors including the NMDA receptor. JNK’s role in the post-synaptic compartment is well characterized, while its pre-synaptic role remains unexplored. The project aims to characterize the pre-synaptic role of JNKs and its scaffold proteins involved in the control / release of NMDA-dependent glutamate.

 

Selected Publications

 

Targeting SUMO-1ylation Contrasts Synaptic Dysfunction in a Mouse Model of Alzheimer’s Disease. Marcelli S, Ficulle E, Iannuzzi F, Kövari E, Nisticò R, Feligioni M. Mol Neurobiol. 2017 Oct;54(8):6609-6623. PubMed

Presynaptic c-Jun N-terminal Kinase 2 regulates NMDA receptor-dependent glutamate release. Nisticò R, Florenzano F, Mango D, Ferraina C, Grilli M, Di Prisco S, Nobili A, Saccucci S, D’Amelio M, Morbin M, Marchi M, Mercuri NB, Davis RJ, Pittaluga A, Feligioni M. Sci Rep. 2015 Mar 12;5:9035. PubMed

Protein SUMOylation modulates calcium influx and glutamate release from presynaptic terminals. Feligioni M, Nishimune A, Henley JM. Eur J Neurosci. 2009 Apr;29(7):1348-56. PubMed