CROSS-NEUROD CONSORTIUM

- UNIT 1 (Coordinator): University of Milan (UNIMI), Neural Stem Cell Lab.

The Neural Stem Cell Lab (at Pathophysiology and Transplantation Dept., UNIMI), PI Prof. Stefania Corti, has specific experience in developing research activity in MN disorders, focussing on stem cell and cellular and molecular therapeutic approaches. This group has established a significant track record of research activities in therapeutic development of cell transplantation, and in the investigation of molecular mechanisms of ALS, SMA and Spinal Muscular Atrophy with Respiratory Distress (SMARD1); it has also established many collaborations with National and International institutions. Since 1994, the Neural Stem Cell Lab has offered meaningful contributions to stem cell and neurodegenerative disease fields providing, in particular, the first assessment of cellular approaches for two infantile MN diseases, SMA and SMARD1. The position of the lab, at the interface between clinical medicine and research, provides a unique platform to conduct further innovative translational research that can advance therapy for neurological diseases. The scientific results of the Neural Stem Cell Lab for both basic and clinical research have been published in high citationrating peer reviewed journals.  Prof. Corti will coordinate the consortium (WP1) and contribute to dissemination and training (WP6). Prof. Corti has already coordinated a successful IRSES project, NO MND, within the previous call together with Prof. Re and Dr Papadimitriou and Dr Stefanis.

- UNIT 2: Columbia University, Motor Neuron Center (MNC).

In the last years, Re’s and Przedborski’s Labs have performed a cutting-edge research regarding ALS, focusing on the role of astrocytes in F/SALS. Their seminal paper reported for the first time that astrocytes carrying a mutated SOD1 gene induce MN death, indicating that astrocytes may contribute to ALS by releasing a toxic factor, damaging neurons. Przedborski’s Lab found that the soluble toxic factor released by astrocytes expressing a mutated form of SOD1 kill only the neurons that degenerate in ALS, but not other types of neurons. The identification of this toxic factor will open the way to develop new strategies for ALS treatment. More recently, they have demonstrated that SALS patients’ astrocytes exhibit the same toxicity to MNs as FALS rodent astrocytes, and unravelled for the first time that both Sand FALS astrocytes induce MN death through Necroptosis, a programmed form of Necrosis. Re and Przedborski’s Lab cooperate with different important institutions in USA and Europe. Serge Przedborski is also Co-director of the MNC. This institution, creating synergistic, large-scale programs for target discovery and functional analysis in an intellectual, collegial and stimulating environment, facilitates the speedy transfer of research and preclinical findings to MND patients.

- UNIT 3: Biomedical Research Foundation, Academy of Athens (BRFAA).

Dr. Leonidas Stefanis is the director of the Neurodegenerative Diseases Group (Division of Neuroscience) at the BRFAA. His primary focus is to assess the mechanisms of neurodegeneration in the context of PD. He is currently participating in multiple international research consortia for the study of α-synuclein biology (NEURASYN) and familial forms of Parkinson’s disease (MeFOPa). Dr. Papadimitriou returned to Greece from MNC in 2009. Harnessing the capabilities of Stefanis’ Lab, as well as the facilities and resources of BRFAA, Dr. Papadimitriou’s long-term goal is the establishment of the first Motor Neuron Disease Research Centre in Greece, which will coordinate with the various Clinical Neurology departments not only within Athens, but also throughout Greece, to develop an overall research strategy that currently does not exist in this country. This will facilitate the recruitment of patients for genetic testing and the collection of tissues (e.g. skin fibroblasts, CSF, PBMCs, plasma) for the purposes of this project. A similar collaborative effort is currently ongoing for the collection of various samples from familial PD patients. Dr. Hardy Rideout, another key member of the group, is focused on neurodegeneration and cell death pathways in familial forms of PD caused by mutations in LRRK2, and his recent work characterized the activation of caspase-8 associated death pathways by mutant forms of LRRK2, the first demonstration of a specific cell death pathway in models of familial PD. The expertise in PD, cell death pathways and in particular caspase-8 dependent signaling (which complements the expertise of Dr. Re’s group in necroptotic death signaling in motor neurons from models of FALS) will be of great benefit for certain aspects of this project.

- UNIT 4: Ca’ Granda Foundation Ospedale Maggiore Policlinico (POLI).

Movement disorders Unit Movement disorder unit at IRCCS Ca’ Granda Foundation is devoted to the study and treatment of extrapyramidal diseases, in particular PD. Dr. Di Fonzo, the PI, is an expert in PD and in differentiation of pluripotent stem cells with a particular focus on dopamine neurons. He has already generated PD-patient iPSC lines with mutations in LRRK2 (PARK8) and PINK1 (PARK6), that will be available for experimentation. He contributed to the identification of LRRK2 as PD causative gene. He is a neurologist interested in unravelling the molecular mechanisms that control key processes in PD using stem cell as a model. His Lab has already generated midbrain organoids. The creation of this in vitro disease model provides a powerful platform for studying Parkinson’s mechanisms and novel therapeutic strategies. Dr. Di Fonzo's Lab has been published in high citation-rating peer reviewed journals and cooperates with different important institutions in Europe and overseas. The collaborations made possible by the CROSS-NEUROD network will accelerate the translation of basic Parkinson’s research into clinical treatments for the disease. Within the current consortium, movement disorder unit at IRCCS Ca’ Granda Foundation will generate the organoids from PD patients iPSCs harboring diseaseinducing mutations (WP2).