title: Protein misfolding and aggregation in Parkinson's disease.
abstract: Protein aggregation as a result of misfolding is a common theme underlying neurodegenerative diseases. In Parkinson's disease (PD), research on protein misfolding and aggregation has taken center stage following the association of alpha-synuclein gene mutations with familial forms of the disease, and importantly, the identification of the protein as a major component of Lewy bodies, a pathological hallmark of PD. Fueling this excitement is the subsequent identification of another PD-linked gene, parkin, as a ubiquitin ligase associated with the proteasome, a major intracellular protein degradation machinery that destroys unwanted, albeit mainly soluble, proteins. Notably, a role for parkin in the clearance of insoluble protein aggregates via macroautophagy has also been implicated by more recent studies. Paradoxically, like alpha-synuclein, parkin is also prone to misfolding, especially in the presence of age-related stress. Similarly, protein misfolding can also affect the function of other key PD-linked genes such as DJ-1, PINK1, and perhaps also LRRK2. Here, we discuss the role of protein misfolding and aggregation in PD, and how impairments of the various cellular protein quality systems could precipitate these events and lead to neuronal demise. Towards the end of our discussion, we also revisited the role of Lewy body formation in PD.
authors.affiliation: Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore.
authors.forename: Jeanne M M
authors.initials: JM
authors.lastname: Tan
authors.forename: Esther S P
authors.initials: ES
authors.lastname: Wong
authors.forename: Kah-Leong
authors.initials: KL
authors.lastname: Lim
mesh_terms: D001343:Autophagy; D001921:Brain / Q000378:metabolism; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D051844:alpha-Synuclein / Q000235:genetics
chemical_list: D051844:alpha-Synuclein