Open Access Senior Thesis
Bachelor of Arts
W.M. Keck Science Department
2019 Paige M Brodrick
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the progressive death of dopaminergic neurons present in the substantia nigra. The clinical presentation of PD includes tremors, slowed movement (bradykinesia), muscle and limb rigidity, and difficulty with walking and balancing. While many environmental factors can affect the onset and progression of the disease, genetic mutations have a large influence. Of the identified PD-linked genetic mutations, mutations in the leucine-rich repeat kinase 2 (LRRK2) are one of the most common genetic causes of PD. Located in endosomes, LRRK2 has been shown to play a role in the sorting and endocytosis of synaptic vesicles, a process that is largely mediated by the retromer complex. Mutations in Vps35, a core component of the retromer cargo-recognition complex, have also been identified as a significant cause of late-onset autosomal dominant familial PD. While the exact molecular mechanisms by which LRRK2 and Vps35 mutations induce PD remain largely unknown, their influence on several cellular processes, including vesicular trafficking and breakdown, and endosomal sorting and recycling, strongly implicate the retromer and autophagy in PD pathology. Recent findings that transgenic expression of Vps35 is able to rescue the PD-related phenotypes caused by LRRK2 mutant forms provide further insight into the interplay of these genes in the context of PD and point to these -genes as potential therapeutic targets. This review outlines the current studies involving these genetic mutations and their interactions with various cellular processes and pathways so as to gain a better understanding of the molecular mechanisms underlying PD pathology for the ultimate purpose of developing safe and effective treatments for PD.
Brodrick, Paige, "A Composite Review of the Proposed Molecular Mechanisms and Genetic Components Underlying Parkinson’s Disease" (2019). Scripps Senior Theses. 1337.