SUMMARY
The Translational Neuroproteomics Laboratory, led by Wilfried Rossoll, Ph.D., studies molecular pathomechanisms of abnormal protein aggregation in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia and Alzheimer's disease. The dysfunction, mislocalization and accumulation of specific proteins into insoluble aggregates in affected brain regions are the defining hallmarks of these age-related proteinopathies.
In previous studies, Dr. Rossoll and colleagues have studied how sequestration of cellular proteins into these aggregates can cause defects in molecular pathways and identified cellular defense mechanisms against the formation of toxic inclusions. These findings support the hypothesis that disease-causing aggregates contain important targets for the development of therapies, including modifiers of protein aggregation, mediators of aggregate toxicity, and diagnostic markers of cellular dysfunction and disease.
Members of Dr. Rossoll's Translational Neuroproteomics Laboratory use autopsy brain tissue to determine the composition of neuropathological aggregates. They also use in vitro and in vivo model systems to gain a mechanistic understanding of how these aggregates form and how to reverse and prevent these pathological changes. The long-term goal of these studies is to translate these findings into new therapeutic approaches to treat and prevent proteinopathies.
Focus areas
- Development of spatial proteomics methods. In collaboration with the Mayo Clinic Brain Bank and multi-omics mass spectrometry experts, Dr. Rossoll's team is developing proximity labeling and microscopy-based proteomics profiling methods to determine the molecular composition of specific cell types and subcellular structures at high spatial resolution in brain tissue.
- Molecular profiling of neuropathological aggregates. Dr. Rossoll's laboratory is using mass spectrometry-based methods to establish proteomic profiles of neuropathological aggregates in autopsy brain tissue and disease models to investigate how they change over the course of the disease. The laboratory also is comparing how people with fast disease progression differ from those presenting with resilience to neurodegeneration.
- Investigating mechanisms of abnormal protein aggregation. 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 ALS, frontotemporal dementia, Alzheimer's disease and related conditions. Studies in the laboratory seek to gain a detailed understanding of mechanisms that regulate abnormal protein aggregation and how to prevent the pathology from occurring and spreading across the brain.
- Translational research on modifiers of protein aggregation. Dr. Rossoll's team discovered potent modifiers of the mislocalization and pathological phase transitions of disease proteins into insoluble aggregates. The Translational Neuroproteomics Laboratory is using cutting-edge techniques to study how these protective factors can reduce the formation of pathological protein aggregates in cell and animal models of proteinopathies.
Significance to patient care
The unmet need for effective therapies to treat the growing number of patients with age-related neurodegenerative diseases is creating mounting personal and financial burdens to patients and caregivers. These diseases occur when specific proteins are misfolded and accumulate as insoluble inclusions in the brain, affecting how neurons connect and the brain functions. A decline in the ability of the aging brain to clear toxic protein aggregates speeds this process. Research in the Translational Neuroproteomics Laboratory focuses on directly targeting these pathological inclusions by finding new modifiers of protein aggregation and harnessing their activity to develop effective therapeutic strategies for patients with neurodegenerative disorders.
Professional highlights
- Director, Multi-Omics Mass Spectrometry Core Laboratory, Mayo Clinic, 2024-present.
- Standing member, Cellular and Molecular Biology of Neurodegeneration Study Section, National Institutes of Health, 2024-present.
- Associate editor, Molecular Neurodegeneration, 2020-present.
- Associate director, Laboratory of Translational Cell Biology Stem Cell Laboratory, Emory University School of Medicine, 2012-2017.