Parkinson's Disease

• Published in: The FASEB journal Vol. 36 Suppl 1
• Main Authors: Bai, Kathleen, Cai, Ziming, Cherif, Ibrahim, Compaore, Faltas C, Fujikawa, Ayaka, Hao, Delilah, Jia, Rachel, Koziakova, Sabina C, Liu, Lenore, Qiu, Elaine, Ramirez, Victoria, Christensen, Anna, Zhang, Josh, Greig, James, MacGillivray, Brendan C
• Format: Journal Article
• Language: English
• Published: United States 01.05.2022
• ISSN: 1530-6860

Parkinson's disease (PD) is a neurodegenerative disease that involves a progressive loss of dopaminergic neurons within the substantia nigra. Patients with PD experience a loss of motor function over time. In normal patients, muscle contractions are driven by action potentials through the binding of the neurotransmitter dopamine. Disruptions to dopaminergic activity would thus result in less efficient contractions. Patients with Parkinson's can experience akinesia, tremors and other motor dysfunction. Glucocerebrosidase (GCase), specifically β-GCase, is a lysosomal enzyme involved in sphingolipid metabolism. β-GCase falls under the hydrolase classification, allowing it to catabolize glucosylceramide (GlcCer) into glucose and ceramide. β-GCase consists of 497 amino acid glycoproteins within its four domains. The glucocerebrosidase gene (GBA) mutations are often associated with Gaucher disease. However, β-GCase synthesized from mutated GBA1 is often studied as a biomarker for PD susceptibility. In a healthy cell with the non-mutated GBA gene, the GBA gene would be transcribed into mRNA and then transported out to the rough Endoplasmic Reticulum, where GCase is then synthesized. Lysosomal integral membrane protein-2 (LIMP2) is a protein that transports GCase through the Golgi Apparatus and transfers the β-GCase into a late endosome. When the late endosome fuses with a lysosome, where β-GCase can hydrolyze its substrates. Mutated β-GCase may affect this autophagy pathway. This research will explore how mutated β-GCase may disturb lysosomal functions, which would consequently lead to the aggregation of alpha-synuclein (ASN), a protein that regulates synaptic vesicle trafficking and subsequently releases dopamine. Therefore, the detection and accumulation of mutated lysosomal enzymes, such as β-GCase, in the cerebrospinal fluid might serve as biomarkers for Parkinson's Disease.