We seek to define the molecular mechanisms that underlie a broad spectrum of multisystem proteinopathies that includes 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 proteinopathies appear to be distinct clinical entities affecting distinct cell types, they share some common underlying pathogenic mechanisms that lead to vulnerabilities in muscle, brain, and/or spinal cord neurons. We dissect the molecular pathways, using both global and protein-targeted approaches, that lead to aberrant toxic aggregates that form the defining pathological hallmarks of these disorders. Using a combination of biochemistry, proteomics, genetics, and in vivo animal experiments, we identified several new biochemical mechanisms that initiate protein aggregation and trigger disease pathogenesis. For example, we uncovered lysine acetylation as a modification (PTM) that has a surprising impact on protein aggregation in both Alzheimer’s and also ALS patients. Our studies raise the intriguing possibility of modification-targeted therapies to suppress pathology in a range of degenerative diseases and possibly in the aged brain itself. By uncovering the mechanistic details that surround abnormal protein aggregation in “vulnerable” cell types, we can begin to devise new therapeutic approaches against these debilitating diseases.