Research
Dr. Rossoll's Translational Neuroproteomics Lab focuses on deciphering the molecular mechanisms that drive neurodegenerative proteinopathies and translating these discoveries into new therapeutic strategies.
Profiling the molecular composition of neuropathological aggregates
A hallmark of neurodegenerative diseases is the accumulation of specific proteins into insoluble aggregates in the brain cells of affected patients. Yet the precise composition and functional role of coaggregating proteins and associated cofactors remain poorly understood. The Translational Neuroproteomics Lab develops and applies advanced mass spectrometry-based spatial and proximity proteomics methods to define the molecular profiles of these aggregates in human brain tissue and disease models.
The team has established probe-dependent proximity profiling (ProPPr) as a powerful approach to characterize neuropathological aggregates in fixed brain tissue. Also, the team is using laser capture microscopy for deep visual proteomics and the Syncell Microscoop as a spatial optoproteomics platform to map disease-relevant proteins at subcellular resolution.
Previous work from the lab has revealed that neuropathological inclusions contain modifiers of protein aggregation and mediators of neurodegeneration, highlighting new therapeutic targets and biomarker candidates. To extend these capabilities across Mayo Clinic's Florida campus, Dr. Rossoll also serves as founding director of the Multiomics Mass Spectrometry Core.
Investigating mechanisms of protein aggregation in neurodegenerative disease
Pathological aggregates consist of aggregation-prone proteins such as TDP-43 and tau, which are central to the pathogenesis of amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer's disease. These aggregates also sequester essential cellular components, thereby disrupting molecular pathways and accelerating neurodegeneration.
Dr. Rossoll's team discovered that cytoplasmic TDP-43 aggregates trap components of the nucleocytoplasmic transport machinery, leading to transport defects that further exacerbate TDP-43 mislocalization and toxicity. To dissect these mechanisms, the team is developing improved cellular and in vivo models of proteinopathies. Collaborations with the Cryo-EM Core at Florida State University enable structural comparisons between experimental and patient-derived protein assemblies.
Developing nuclear transport factors as modifiers of TDP-43 pathology
The Translational Neuroproteomics Lab aims to define the molecular mechanisms that drive protein mislocalization, dysfunction and aggregation and to identify strategies to prevent the initiation and spread of pathology within the central nervous system. The team has discovered that nuclear import receptors (importins) act as potent protective modifiers of TDP-43 aggregation. The team is using complementary approaches of biochemistry, molecular and cell biology, as well as advanced fluorescence microscopy, to uncover how importins can suppress pathology.
To validate therapeutic targets, the team delivers engineered proteins into the central nervous system of preclinical models using adeno-associated virus-based gene therapy and alternative approaches, laying the foundation for future therapy development.