Protein mechanism and therapeutic design in Parkinson's disease: A structural biology perspective

Parkinson's disease (PD) remains one of the most elusive, progressive neurological diseases to treat due to an incomplete understanding of its pathology. Current symptomatic therapies revolve around alleviating symptoms with dopamine replacement therapy; however, this mode of treatment does not always provide long-term relief or address the underlying cause. Thus, there is still a need to better understand the mechanisms of proteins implicated in neurodegeneration as the key to developing disease-modifying treatments. Here we discuss recent advances in our understanding of six protein targets for PD therapy: α-synuclein, LRRK2, GBA1, PARKIN, PINK1, and USP30. For each, we highlight novel structures that shine light both on pathogenic mechanisms as well as novel therapies. We discuss drugs targeting these proteins that are in clinical trials, and how structures are used to improve them.