Research in the laboratory attempts to define pathogenic cellular and molecular mechanisms involved in synucleiopathies, in particular Parkinson's disease and multiple system atrophy, amyotrophic lateral sclerosis, and Alzheimer's disease. Our work focuses on the interactions between glia and neurons. We are constantly developing new and robust human stem cell-based models which we utilize to understand cell autonomous and non-cell autonomous processes that lead to neuronal damage.
By generating iPSCs from patients suffering familial and sporadic forms of the diseases, we aim to elucidate causative mechanisms leading to neural cell dysfunction, and neurodegeneration.
Our cutting-edge approach will allow for the identification of new molecular targets, which could be used for the development of new diagnostic tools for early diagnosis, as well as for the stratification and recruitment of patients for future clinical trials.
Photo: Laurent Roybon lecturing at the 3rd Nordic Neuroscience meeting in Helsinki (June 2019)
Synucleinopathies Parkinson's disease and multiple system atrophy
Synucleinopathies, which include Parkinson’s disease and multiple system atrophy, are neurodegenerative diseases where alpha-synuclein protein is often aggregated in different neural cell types. Experimental evidence suggests that the cellular specificity of the development of the aggregates may depend on the structure and properties of aggregated aSYN and on the proteome of the cells in which they form. Moreover, data suggest that synucleinopathies may arise in response to cellular and non-cellular autonomous effects, including environmental stressors and aging, and are accompanied by the formation of aggregates involved in the disease development and progression. Our overarching goal is to decipher the relationship between cell specific cellular dysfunction and aggregate formation, to gain insights onto the origin, development and progression of synucleinopathies. To this aim, we employ a multidimensional approach to decipher processes governing cellular dysfunction and protein aggregation in human brain cell types generated from patient pluripotent stem cells, grown as 2D monolayers and 3D minibrains, in vitro and in vivo.
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly resulting in mental and cognitive decline, loss of memory, and eventually leading to significant disability. Despite the generation of transgenic animal models of Alzheimer’s disease (AD), our understanding of pathological events leading to AD remains incomplete due to the complexity of the disease and the interaction between environmental factors and human aging. This has proved impossible to model by using only animal-derived material. Hence, the absence of reliable models reconstructing bona fide diseased microenvironment, and the lack of robust readout assays to reliably evaluate mechanisms of AD have hampered the development of efficient interventions. Recent studies indicate that human neural stem-cell (hNSC)-derived 3D culture systems recapitulate full AD pathology when mutations are artificially introduced. Also, transplanted hNSCs have the ability to integrate functionally into the rodent brain. Based on these fundamental observations, we generated advanced human cellular models allowing for the purification and identification of specific neural cell types involved in the disease, which we use to generate robust readouts beyond those currently existing. The labeling of patient neural cells generated through reprogramming technologies allows access to homogenous cultures, which grown alone or in mixed 3D cultures, is used to address disease relevant phenotypes both in vitro, and in vivo. Such approaches allow accurate deciphering of the phenotypic heterogeneity of cell dysfunction and death processes, whether these pathogenic mechanisms rely on cell-autonomous effects and/or propagation of pathogenic proteins, and the contribution of neuroinflammation by glial cells as determinants of disease progression. Our clinically relevant approaches will help to identify relevant disease phenotypes for the development of biomarkers for early diagnosis and for patient stratification and their recruitment in future clinical trials. Our discoveries will also allow identification of specific molecular targets for better design of drugs and application of personalized treatments to people with AD.
Motoneuron disease amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is an incurable adult onset neurodegenerative disease affecting motor neurons (MNs). There is still no cure for ALS, which invariably results in the death of the patients within few years after diagnosis. MN loss implicates cell autonomous processes, as well as non-cell autonomous processes mediated by glia, suggesting that to be effective, a therapy for ALS should target both neurons and glia. Under disease condition, glial cells such as astrocytes become reactive and toxic to MNs, in addition to losing the expression of the glutamate transporter 1 (GLT1), which function is to prevent overstimulation of glutamate receptors in MNs, therefore neuronal injury known as excitotoxicity. Thus, a possible therapy for ALS would be the delivery prior to or at onset, of factors that would prevent astrocytes toxicity and reactivity, as well as loss of GLT1, in addition to promoting MN survival. Our goal is to develop a viral-mediated strategy to deliver therapeutic gene candidates to halt disease progression. To this aim, we are developing in vitro an in vivo models, where such strategy can be tested.