PROJECT SUMMARY / ABSTRACT Neurodegenerative diseases, which include Alzheimer’s (AD), primary tauopathies, and other dementias, affect more than 6.5 million Americans with significant challenges for families and society. The hallmark of neurodegenerative disease is the stereotypical deposition of misfolded protein in the brain, with primary tauopathies showing tau accumulation in neurons and glia. The basis for cellular dysfunction in primary tauopathies is not well understood, underscoring an important need to broaden the biologic scope of research. Technological advances, based on single-cell whole-genome sequencing (scWGS) on human brain tissue, now allow examination of previously inaccessible aspects of the genome of individual cells in the brain. My colleagues and I have found that neurons in individuals with AD show greater somatic single-nucleotide variants (sSNV) in their genomes than in individuals without AD. From mutational signature analysis, specific causes of somatic mutations differed in AD, implicating oxidative stress and additional signal suggesting other cytopathologic events. This study will assess somatic mutation in the setting of primary tauopathies, based on four complementary themes. I will examine the process of genome-wide somatic mutation in neurons and glia in brain from individuals with primary tauopathy, and in a cellular model system we can dissect specific contributors to mutational mechanisms. I will also use single-cell functional studies to probe mechanisms of cell death in primary tauopathy. Throughout the study, I will use new single-cell cytopathological methods to study the role of tau in somatic mutation and broader disease mechanisms. With complementary approaches of novel scWGS technology, single-nucleus sorting, and unique human tissue and cellular system resources, I will examine the mechanistic role of somatic mutations in primary tauopathy. This work stands to address fundamental questions in neurodegeneration and develop new approaches for identification of disease mechanisms, with the potential for broad application for better diagnostic and therapeutic options.

PROJECT NARRATIVE Alzheimer’s disease (AD) and other neurodegenerative diseases involve a loss of brain function and brain cells over time and eventually cause death, affecting a substantial amount of the population as we age. Recent research has found that brain cells build up new mutations in the DNA (known as somatic mutations) in AD, which appears to harm the brain cells. This proposal will test for somatic mutations in another neurodegenerative disease, primary tauopathy, using advanced studies of single cells to look at how mutations relate the buildup of the misfolded protein tau.