Protein misfolding disorders and macroautophagy

Abstract

A large group of diseases, termed protein misfolding disorders, share the common feature of the accumulation of misfolded proteins. The possibility of a common mechanism underlying either the pathogenesis or therapy for these diseases is appealing. Thus, there is great interest in the role of protein degradation via autophagy in such conditions where the protein is found in the cytoplasm. Here we review the growing evidence supporting a role for autophagic dysregulation as a contributing factor to protein accumulation and cellular toxicity in certain protein misfolding disorders and discuss the available evidence that upregulation of autophagy may be a valuable therapeutic strategy.

Figure 1

A model for autophagy regulation in proteinopathies. An interconnected system exists in which autophagy is able to control the levels of intracytoplasmic aggregate-prone proteins (green arrow). However, these proteins are also able to control levels of autophagy (blue arrows). Additionally levels of autophagy are also able to be regulated using drugs (red arrow). The balance between these factors will alter cell survival.