RESEARCH OVERVIEW
The overarching goal of the Didonna Lab consists in elucidating the mechanisms underlying central nervous system (CNS) autoimmunity, with an emphasis on disease progression and neurodegenerative phenotypes. For this purpose, the lab routinely employs in vivo models of neuroinflammation in combination with cutting-edge "omics" technologies (Next-Generation Sequencing, mass-spectrometry proteomics) and the latest approaches for genetic manipulation in mice. A consistent part of the lab research efforts is focused on multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). In fact, MS is perhaps the most paradigmatic autoimmune disease and provides an excellent framework to investigate the interactions between the immune and nervous systems in health and disease.
In parallel to our work on MS, the lab is also interested in elucidating the role played by the immune compartment in the etiopathogenesis of disorders that were once considered purely neurodegenerative such as Alzheimer's disease and Parkinson's disease. In particular, we are keen to characterize the contribution of inflammatory stress to protein misfolding in the brain. We also intend to explore the possible involvement of peripheral and CNS resident immune cells in modulating disease susceptibility and clinical manifestations. The main projects that are currently running in the lab are described in the panels below.
THE IMMUNOMODULATORY ROLE OF ATAXIN-1
The genomic region containing the ATXN1 gene is a novel risk locus for MS. This gene encodes ataxin-1, a polyglutamine protein that is classically associated with the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1). We have recently shown that ataxin-1 also exerts a protective activity in a preclinical model of MS. This function is associated with an immunomodulatory role mainly targeting the B cell compartment. In the future, we will build on these findings to carry out a comprehensive characterization of ataxin-1 activities in the immune system upon CNS autoimmunity.
TAU IN CHRONIC NEUROINFLAMMATION
The goal of this project is to explore the role played by the neuronal cytoskeleton in the physiological response to neuroinflammation. We have recently shown that the microtubule-associated protein (MAP) tau may represent a key component of a homeostatic mechanism evolved to preserve axonal integrity against inflammatory stress. In the future, we intend to further dissect tau neuroprotective activity by elucidating its contribution to maintain synaptic functionality in a pro-inflammatory milieu. Understanding the adaptive response that neurons engage to cope with neuroinflammatory challenges might pave the way to novel therapeutic solutions aimed at boosting the physiological mechanisms of protection.
HLA IN PARKINSON'S DISEASE
Genetic risk in PD has been mapped to the HLA locus, which encode highly variable cell surface immune receptors, but precise allelic associations have been difficult to infer due to limitations in genotyping methodology. To overcome this limitation, we have used deep sequencing to reveal specific variants conferring either risk or protection in PD. We will use this new knowledge to address the molecular mechanisms by which these HLA genes modulate disease phenotypes in PD pathogenesis.
NEUROENDOCRINE SIGNALING IN AUTOIMMUNE DEMYELINATION
The endocrine system is a complex network of glands and organs located throughout the body that uses hormones to coordinate cellular activity and maintain homeostasis across a broad range of physiological states. We have recently found that the hypothalamus, a critical integration and regulation center of neuroendocrine signaling, is an early target of pathology in the EAE paradigm. We also showed that the structure and function of the main endocrine glands are selectively disrupted upon disease. Fueled by these observations, we are interested in further dissecting the contribution of endocrine dysfunction to MS manifestations as well as the role of endocrine-disrupting chemicals in modulating the risk of disease.
