Molecular pathogenesis of neurodegeneration
Our research is focused on understanding the molecular mechanisms leading to neurodegenerative disorders, such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). ALS affects motor neurons and leads to progressive paralysis, while FTLD leads to language and behavioral dysfunction. Both diseases are devastating and cause death within a few years from diagnosis. Recent discoveries have shown that the two diseases are genetically and pathologically linked, perhaps caused by the same molecular mechanism that harms neurons and causes them to progressively malfunction and die. What is the molecular mechanism triggering neuronal dysfunction and death in ALS and FTLD? What are the mechanistic pathways driving the relentless progression of neurodegeneration in ALS and FTLD?
Mutations in a number of essential proteins, such as SOD1, TDP-43, FUS/TLS and a newly identified protein of unknown function – tentatively called C9orf72 – have been found in patients with familial forms of ALS and/or FTLD, indicating that the misregulation of each of these proteins may be responsible for initiating the cascade of events leading to neurodegeneration. Importantly, protein aggregation of TDP-43 appears to be a common finding in the vast majority of sporadic ALS cases, in the absence of mutations in any of the known ALS-causing genes. In fact, protein misfolding and aggregation is the common delineator of pathogenic changes characterizing ALS and FTLD, as well as other neurodegenerative diseases. Yet the role of protein aggregation in the pathogenesis of these diseases remains unknown.
A-B. Examples of TDP-43 aggregates (in red) found in affected spinal motor neurons of ALS patients C. Healthy spinal motor neurons in a control individual, lacking TDP-43 aggregates. D-G. Magnifications of ALS motor neurons with TDP-43 aggregates. Modified from .
In order to understand the molecular pathogenesis and to identify potential opportunities for therapeutic interventions for ALS and FTLD, we combine high-throughput sequencing with basic biochemistry methods and organotypic slice cultures as well as human cells. We are particularly interested in mimicking the molecular events triggered by aggregation of ALS/FTLD-linked proteins by inducing the misfolding and aggregation of their native forms, following a prion-like paradigm. We envision building a reliable model to study ALS and FTLD, and to identify mechanistic pathways driving their perpetuating progression.
Self-propagated aggregation in ALS and FTLD. TDP-43 is a primarily nuclear RNA-binding protein, which gets incorporated in stress granules. The latter are cytoplasmic foci forming via the ordered aggregation of several RNA-binding proteins complexed with RNA molecules. This physiologic reaction to cellular stress may be the initial trigger for pathogenic inclusion formation of TDP-43. Upon chronic cellular stress and defects in stress granule disassembly, the functional prion-like conformational changes of TDP-43 may transform into pathogenic self-perpetuating, irreversible aggregation. It is unknown whether TDP-43 aggregates can spread from cell to cell to initiate misfolding and aggregation of native TDP-43 proteins. Modified from .
|Since 2013:||SNSF Assistant Professor, Institute of Molecular Life Sciences, University of Zurich, Switzerland|
|2008–2013:||Postdoctoral Fellow with Don W. Cleveland, University of California in San Diego, CA, USA|
|2006–2008:||Postdoctoral Fellow with Adriano Aguzzi, University Hospital of Zurich, Switzerland|
|2007:||Visiting Scientist, Prion Blood Testing Group, Novartis Diagnostics, Emeryville, CA, USA|
|2001–2006:||PhD in Molecular Biology/ Neuroscience with Adriano Aguzzi, University Hospital of Zurich, Switzerland|
|1996-2001:||BSc/MSc in Pharmaceutical Sciences, Aristotle University of Thessaloniki, Greece|
Awards & Honors
|EMBO, Young Investigator Program|
|2017:||ALS Association, Investigator Initiated Award|
|2017:||SNSF Professorship extension|
|2015:||NCCR RNA & Disease, Junior Investigator Award|
|2015:||Georg-Friedrich Götz Prize, University of Zurich|
|2013:||HFSPO, Career Development Award|
|2011:||NIH, Pathway to Independence Award K99|
|2008:||HFSPO, Long Term Postdoctoral Fellowship|
|2008:||SNSF Fellowship for advanced researchers, (gratefully declined)|
|2005:||University of Zurich, Career Award|
|2001:||EMBO, Short Term Fellowship|