Polyglutamine (polyQ) diseases are a group of neurodegenerative disorders caused by aberrant expansion of CAG trinucleotide in the coding sequence of different disease proteins. This CAG trinucleotide repeats lead to the abnormal polyQ expansion in the translated proteins, which may cause protein misfolding and aggregation. Protein aggregation or inclusion formation is a common feature shared by diverse neurodegenerative diseases. Aggregation of polyQ-expanded proteins can sequester other interacting proteins or RNA into the insoluble aggregates or inclusions, which may result in decrease in the soluble pools of both polyQ proteins and other sequestered proteins or RNA, leading to the loss of biological function. According to the interaction modes, we classified the sequestration effects of protein aggregates into four distinct types: protein (including polyQ protein) co-aggregation; specific domain/motif-mediated sequestration (including modified ubiquitin and others); RNA-mediated sequestration; and sequestration of molecular chaperones. Thus, aggregation of the polyQ-expanded proteins and sequestration of cellular essential proteins may be the major causes for cytotoxicity and neurodegeneration.