Overview

The Translational Neuroproteomics Laboratory of Wilfried Rossoll, Ph.D., is dedicated to studying the role of aberrant protein aggregation in the pathogenesis of neurodegenerative disorders and developing therapeutic strategies to treat these proteinopathies.

Neurodegenerative diseases are proteinopathies

Neurodegenerative diseases are defined by the pathological phase transition of specific proteins from soluble, liquidlike condensates into solid fibrils that accumulate in highly insoluble aggregates in affected brain regions. Current research in Dr. Rossoll's laboratory focuses mainly on common proteinopathies that are characterized by increased aggregation of the RNA-binding protein TDP-43 or the microtubule-binding protein tau.

TDP-43 proteinopathies include diseases such as amyotrophic lateral sclerosis, frontotemporal lobar degeneration and limbic-predominant age-related TDP-43 encephalopathy. Tauopathies include Alzheimer's disease and the primary tauopathies: progressive supranuclear palsy, corticobasal degeneration and Pick's disease. Ongoing collaborations also include studies on synucleinopathies with aggregates of the synaptic protein α-synuclein, such as Parkinson's disease and Lewy body dementia. While these disorders are often studied separately, the frequent presence of different aggregates in the brain of Alzheimer's disease and related dementias suggests that copathologies may play an important role in modulating the disease process.

Defining the molecular pathology of neurodegenerative diseases

Despite recent advances in proteomics technologies, the specific molecular composition of neuropathological aggregates in the brains of patients who are affected is poorly understood. To address this knowledge gap, newly developed, state-of-the-art, mass spectrometry-based proteomics methods and high-resolution fluorescence microscopy are being employed to determine the composition of neuropathological aggregates and specific cell types in human brain tissue. These studies aim to identify modifiers of aggregation, mediators of neurodegeneration and markers for diagnosis.

Understanding molecular disease mechanisms of proteinopathies

While neuropathological studies using human autopsy brain tissue are a valuable resource to gain a better understanding of the molecular pathology, disease models are needed for hypothesis-driven functional studies to investigate the disease process. To gain a better understanding of disease mechanisms, Dr. Rossoll's research team uses cell culture and animal models of neurodegenerative disease, including organotypic brain slice cultures and human stem cell-derived neurons.

An important technical approach in this laboratory is the use of high-resolution fluorescence microscopy to study disease processes on a cellular level. The Translational Neuroproteomics Laboratory also uses genetic mouse models to study how the protein composition of specific cell types in the central nervous system changes as the disease develops. In collaboration with the Neuropathology and Microscopy Laboratory and Translational Neuropathology Laboratory, cellular phenotypes identified in the laboratory are extensively validated by comparison to the actual pathology present in patient tissues.

Targeting modifiers of protein aggregation to develop therapies

Based on the identification of disease modifiers and drawing from mechanistic studies to understand their mode of action, the Translational Neuroproteomics Laboratory seeks to develop therapies for neurodegenerative proteinopathies. The laboratory delivers therapeutic proteins via viral vectors into preclinical models of neurodegenerative diseases to validate these targets for therapy development.