Our research is focused on molecular mechanisms that underlie a broad spectrum of diseases characterized by protein aggregates. These include diseases of the brain, spinal cord, and muscle: for example, myopathies (sporadic inclusion body myositis, or sIBM), amyotrophic lateral sclerosis (ALS) (a motor neuron disease), and dementia (Alzheimer’s disease, AD, and related tauopathies). Although these diseases appear to be distinct (at least clinically) and affect different cell types, strikingly they share common underlying pathogenic mechanisms that lead to cell-type specific vulnerabilities. We seek to uncover these molecular pathways, using both global and protein-targeted approaches, that promote the formation of toxic aggregates that represent the defining hallmarks of all of these disorders. Using a combination of cell biology, biochemistry, proteomics, genetics, and in vivo animal modeling, we identified several pathological mechanisms that drive disease pathogenesis. Ultimately, by uncovering the details that surround protein aggregation in “vulnerable” cell types can we begin to develop new therapeutic approaches against these debilitating diseases. Ongoing drug screening efforts should help guide the above mechanistic insights into effective new drugs that show preclinical efficacy.