Joshua Dubnau, PhD
The primary focus on my lab’s research is the role of retrotransposons (RTEs) and endogenous retroviruses (ERVs) in aging, and in neurodegenerative disorders such as Frontotemporal dementia, Amyotrophic Lateral Sclerosis and Alzheimer’s Disease. This idea has gained traction over the past few years, and a vibrant field of study has emerged with my lab as one of the leaders. We have demonstrated a link between TDP-43, a central protein in such disorders, and control of ERVs/RTEs in a fly disease model. We also demonstrated with a group of collaborators that the same phenomenology is present in post mortem tissues from patients. In the Drosophila model, we are able to conduct mechanistic studies to understand both the mechanisms by which TDP-43 protein aggregation might trigger ERV/RTE expression, and the mechanisms by which their expression may be toxic to neurons and glial cells. We have demonstrated that TDP-43 protein aggregation causes RTE/ERV de-repression, and we also have shown that the converse is true: expression of either fly or human ERVs are sufficient to trigger the onset of TDP-43 aggregation pathology. This indicates that ERV expression and TDP-43 pathology form a positive feedback loop. Further mechanistic studies in my lab have established that ERVs play a key role in mediating the intercellular spread of neurodegeneration within the nervous system. In a Drosophila model, we have established that ERVs are capable of viral transmission between cells, and that this causes the toxic spread of TDP-43 aggregation. This inter-cellular mechanism plays a causal role in the progression of disease phenotypes in the fly model. We have evidence that RTE/ERV expression also triggers a DNA damage mediated cell death pathway, and may trigger inflammatory signaling to trigger systemic effects.
The work in my lab has the potential to inform clinical interventions. Already there are several clinical trials for ALS and FTD, that investigate the ability of FDA approved retroviral drugs to inhibit these endogenous viral like elements.
Professor
(Primary appointment: Department of Anesthesiology)
Director, Center for Developmental Genetics
Joshua.Dubnau@stonybrookmedicine.edu
Center for Molecular Medicine, Room 436
(631) 632-9030
