Dysfunction in Protein Biology

One of the cardinal histological signs of PD is the presence of Lewy bodies: abnormal inclusions composed of aggregated proteins found within neurons in regions of the brain that degenerate in PD. It is contested whether protein aggregation plays a protective role in secluding malformed proteins or a pathogenic role in disease progression.

Diverse regulatory mechanisms act to prevent misfolding and ensure proper protein-protein interactions throughout the stages of protein production. These stages include transcription and translation, post-translational modification, trafficking and degradation. Dysfunction at any of these stages can lead to malformed proteins and aggregation. Defects in the ability of certain neuronal populations to properly regulate protein behavior may cause the specific neurodegeneration and dysfunction associated with PD.

A major constituent of the Lewy body is the protein alpha-synuclein. Overexpression and mutation of the SNCA gene that codes for alpha-synuclein have been implicated as causative factors in rare cases of familial PD. The prevailing theory is that these genetic alterations lead to toxic aggregation of alpha-synuclein, although whether toxicity is triggered by early, soluble oligomeric species of alpha-synuclein or the later stage insoluble fibrils remains a matter of much debate. Genetic studies have also implicated a number of other genes (e.g., parkin, uchl1, ATP13A2) whose protein products play roles in various protein handling pathways, in particular those related to protein degradation pathways of the ubiquitin proteasome system and lysosomal system.