Research
Ongoing research in Dr. Rossoll's Translational Neuroproteomics Laboratory focuses on understanding molecular disease mechanisms and developing novel therapeutic strategies for neurodegenerative proteinopathies.
Profiling the molecular composition of neuropathological aggregates
Neurodegenerative diseases are characterized by the accumulation of specific proteins into detergent-insoluble aggregates. The composition and functional role of coaggregating proteins and associated cofactors in this pathology is poorly understood. Dr. Rossoll's research team is developing and employing mass spectrometry-based local proteomics and proximity proteomics methods to establish the molecular profile of these aggregates in human brain tissue and advanced disease models. To support related research projects at Mayo Clinic in Florida, Dr. Rossoll is the founding director of the Multi-Omics Mass Spectrometry Core.
Previous work from the laboratory has shown that TDP-43 and c9orf72 repeat-associated poly-GA inclusions contain modifiers of protein aggregation and mediators of neurodegeneration that serve as targets for therapy development and biomarkers for the development of diagnostics. The laboratory has established Probe-Dependent Proximity Profiling as a new method to profile and compare the composition of hyperphosphorylated tau inclusions and other neuropathological aggregates in fixed tissue from the Mayo Clinic Brain Bank. In addition, Dr. Rossoll's laboratory is working to establish the Syncell Microscoop as a spatial optoproteomics discovery platform to identify disease-relevant proteins at subcellular resolution.
Identifying mechanisms of protein aggregation in neurodegenerative diseases
Pathological aggregates in the brain can sequester cellular proteins, disrupting molecular pathways and causing neurodegeneration. Research in Dr. Rossoll's laboratory focuses on aggregation-prone proteins such as TDP-43 and tau, which are critically involved in the pathogenesis of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). Studies in the laboratory seek to gain a detailed understanding of molecular mechanisms that promote the dysfunction, mislocalization and aggregation of these disease proteins, and how to prevent the pathology from occurring and spreading across the central nervous system (CNS).
Dr. Rossoll's team has discovered that cytoplasmic TDP-43 aggregates accumulate components of the nucleocytoplasmic transport machinery, causing nucleocytoplasmic transport defects that further accelerate TDP-43 mislocalization and dysfunction and mediate toxic effects of these inclusions. To get a better mechanistic understanding of these processes, Dr. Rossoll's laboratory also is developing improved in vitro and in vivo disease models of proteinopathies. To compare experimental and patient-derived protein structures, Dr. Rossoll and colleagues are collaborating with the cryogenic electron microscopy core at Florida State University.
Nuclear transport factors as modifiers of TDP-43 protein aggregation
The RNA-binding protein TDP-43 plays an important role in cellular RNA metabolism in the nucleus. Its cytoplasmic mislocalization and aggregation is a common feature of not only ALS and FTD but also AD and related dementias.
Dr. Rossoll's laboratory has discovered that nuclear import receptors (importins) can act as potent protective modifiers of pathological TDP-43 aggregation. His team is using cutting-edge techniques in the areas of biochemistry, molecular and cell biology, and fluorescence microscopy to identify ways to prevent the formation of pathological protein aggregates in various disease models, including organotypic brain slice cultures and mouse models.
The laboratory delivers therapeutic proteins via engineered adenovirus-associated viruses to the CNS of preclinical animal models to validate therapeutic targets for potential therapy development in the future.