Leveraging Proteomics to Explore the Molecular Mechanisms of Primary Tauopathies

Primary tauopathies are progressive neurodegenerative diseases characterised by the deposition of aggregated tau in the brain. The molecular mechanisms underlying tau toxicity and neurodegeneration in these diseases are still poorly understood. Proteomics studies of human primary tauopathy brain tissue are beginning to provide insight into molecular mechanisms involved in disease pathogenesis. Here, we review the current landscape of human brain proteomics in three primary tauopathies: progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. For progressive supranuclear palsy, the most well-studied primary tauopathy, we provide a combined analysis of bulk proteomic changes in the brain. From this compilation and additional studies using complementary proteomics approaches, we highlight five highly relevant disease mechanisms in primary tauopathies: mitochondrial dysfunction, synaptic impairment, autophagy and endolysosomal dysfunction, RNA and RNA-binding protein dysregulation, and iron dyshomeostasis. We discuss how each of these mechanisms participates in primary tauopathy pathogenesis and suggest recommendations for future proteomics studies that will advance our understanding of these diseases.