Educational Background
- University of Pennsylvania, Post-Doc
- San Raffaele, PhD
Francesco Lotti, PhD
Associate Professor
Dr. Francesco Lotti is an Associate Professor in Medical Laboratory Sciences. His research focus is the basic biology of RNA-protein homeostasis and how it relates to disease in general and neurodegeneration in particular.
See Contact DetailsResearch Interest
RNA-protein Homeostasis in Healthy and Diseased Neurons
The goal of my laboratory work is to understand the basic biology of RNA-protein homeostasis and how it relates to disease in general and neurodegeneration in particular. Three questions drive our research: (1) How do neurons maintain RNA-protein homeostasis? (2) How do perturbations in RNA-protein homeostasis lead to neurodegeneration? (3) Can modulation of RNA-protein homeostasis be used as a therapeutic tool?
RNA-protein homeostasis generally refers to the post-transcriptional and post-translational processes that maintain the proper cellular repertoire of functional RNA and proteins. In the cell, RNA exists and functions in a complex with proteins (RNA binding proteins or RBPs) that regulate each step of the RNA life cycle, from transcription to degradation. Central to this regulation is the role of several molecular chaperones that ensure the correct interactions between RNA and proteins, while aiding the biogenesis of large RNA-protein complexes (ribonucleoproteins or RNPs). Many key biochemical reactions take place in specialized subcellular compartments that can be visualized as dots or granules containing RNPs. The composition of these RNP granules is highly dynamic and changes dramatically upon environmental perturbations and stress. This plasticity allows the cell to respond rapidly to changing environments, which is particularly important for neurons that are terminally differentiated and non-dividing. To gain a deeper understanding on how neurons maintain RNA-protein homeostasis, we are investigating the signaling pathways that lead to post-translational modifications (PMTs) of RBPs and molecular chaperones and how these modifications regulate the dynamics and functions of RNP granules.
Mutations in genes coding for RBPs and molecular chaperones are being reported in a growing list of neurodegenerative diseases, which includes Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA). A remarkable feature of these disease-causing proteins is their ability to transition between different conformational states. However, this ability comes with a cost as many of these proteins have a high propensity to misfold and to aggregate. Indeed, cytoplasmic and nuclear
aggregates of RBPs are common molecular hallmarks of a large number of neurodegenerative diseases. A fascinating hypothesis, which we are investigating, is emerging on the basis that these aggregates are indicative of and result from pathological transitions in endogenous pathways for RNP assembly and clearance. An important unresolved question is whether these pathological inclusions are causative agents of neurodegeneration or innocent bystanders. We are addressing this question by investigating how the persistence of RNP aggregates affects RNA-protein homeostasis in motor neurons and what is their relationship to the degeneration of these neurons in ALS.
Enabling these studies, our research employs both cellular and animal models as well as a wide range of biochemical, molecular and cell biological methodologies. A combination of genomic interrogation techniques with high-throughput screenings is also used to identify chemical and genetic modifiers of RNA-protein homeostasis to be developed as therapeutic agents. The long-term implications of our research are twofold. First, this work has the potential of revealing novel regulatory networks that govern fundamental cellular pathways for RNP assembly and clearance. Second, understanding the contribution of altered RNA-protein homeostasis to the pathogenesis of neurodegenerative diseases may lead to new methods of diagnosis and therapy for these devastating disorders.
Selected Publications
- Utkina-Sosunova I, Chiorazzi A, de Planell-Saguer M, Li H, Meregalli C, Pozzi E, Carozzi VA, Canta A, Monza L, Alberti P, Fumagalli G, Karan C, Moayedi Y, Przedborski S, Cavaletti G, Lotti*. Molsidomine provides neuroprotection against vincristine-induced peripheral neurotoxicity through soluble guanylyl cyclase activation. Sci Rep. 2024 Aug 20;14(1):19341. doi: 10.1038/s41598-024-70294-w. PMID: 39164364. *Senior author.
- Dermentzaki G, Furlan M, Tanaka I, Leonardi T, Rinchetti P, Passos PMS, Bastos A, Ayala YM, Hanna JH, Przedborski S, Bonanomi D, Pelizzola M, Lotti F*. Depletion of Mettl3 in cholinergic neurons causes adult-onset neuromuscular degeneration. Cell Rep. 2024 Apr 23;43(4):113999. doi: 10.1016/j.celrep.2024.113999. Epub 2024 Mar 30. PubMed PMID: 38554281. *Senior author.
- Suazo KF, Mishra V, Maity S, Auger SA, Justyna K, Petre AM, Ottoboni L, Ongaro J, Corti SP, Lotti F, Przedborski S, Distefano MD. Improved synthesis and application of an alkyne-functionalized isoprenoid analogue to study the prenylomes of motor neurons, astrocytes and their stem cell progenitors. Bioorg Chem. 2024 Apr 16;147:107365. doi: 10.1016/j.bioorg.2024.107365. [Epub ahead of print] PubMed PMID: 38636436.
- Pérez-Torres EJ, Utkina-Sosunova I, Mishra V, Barbuti P, De Planell-Saguer M, Dermentzaki G, Geiger H, Basile AO, Robine N, Fagegaltier D, Politi KA, Rinchetti P, Jackson-Lewis V, Harms M, Phatnani H, Lotti F, Przedborski S. Retromer dysfunction in amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2022 Jun 28;119(26):e2118755119.
- Riboldi GM, Faravelli I, Kuwajima T, Delestrée N, Dermentzaki G, De Planell-Saguer M, Rinchetti P, Le T Hao, Beattie CE, Corti SP, Przedborski S, Mentis GZ and Lotti F*: Sumoylation regulates the assembly and activity of the SMN complex. Nat. Commun. 2021 Aug 19;12(1):5040. *Senior author.
- Mishra V, Re DB, Le Verche V, Alvarez MJ, Vasciaveo A, Jacquier A, Tomas-Doulias P, Greco TM, Nizzardo M, Papadimitriou D, Nagata T, Rinchetti P, Perez-Torres E, Politi K, Ikiz B, Clare K, Corti S, Schiropoulos H, Lotti F, Califano A, Przedborski S: Systematic elucidation of neuron-astrocyteinteraction in ALS using multi-modal integrated bioinformatics. Nat. Commun. 2020 Nov. 4;11(1):5579.
- Osman EY*, Van Alstyne M*, Yen P-F*, Lotti F, Feng Z, Ling KKY, Ko C-P, Pellizzoni L, Lorson CL: Minor snRNA gene delivery in SMA mice links U12 splicing dysfunction to the loss of proprioceptive sensory synapses on motor neurons. JCI Insight 2020 Jun 18;5(12). *Equal contribution.
- Cirrincione AM*, Pellegrini AD*, Dominy JR, Benjamin ME, Utkina-Sosunova I, Lotti F, Jergova S, Sagen J, Rieger S: Paclitaxel-induced peripheral neuropathy is caused by epidermal ROS and mitochondrial damage through conserved MMP-13 activation. Sci Rep. 2020 Mar 4;10(1). *Equal contribution.
- Simon CM*, Van Alstyne M*, Lotti F, Bianchetti E, Tisdale S, Watterson DM, Mentis GZ, Pellizzoni L (2019): Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy. Cell Rep. 2019 Dec 17;29(12). *Equal contribution.
Contact Details
Francesco Lotti