Hiap Chon How
Parkinson’s Disease (PD) is the second most common neurodegenerative disorder which affects an estimated 0.3% of the population worldwide. Prevalence of PD increases exponentially with age (>3% of the population over 80 years old) and is uncommon in population under 50. PD is therefore an aging-associated disorder.
PD patients suffer from tremor, rigidity and slowness at initiating movement, which leads to difficulties in performing routine physical tasks. Approximately 30% of the patients also experience non-motor defects such as loss of olfaction, depression and anxiety. These symptoms are believed to be caused by the degeneration of dopaminergic (DA) neurons in the substantia nigra (SN), which to this day remains incurable. The causes of DA neuron degeneration is generally unknown, with about 90% of the cases happening sporadically and only about 10-15% of cases known to have a genetic link. These genetic forms of PD include mutations in the LRRK2, UCHL1, DJ-1, Parkin, GBA1 and notably SNCA genes. Mutation in SNCA(which encodes for α-synuclein) confers the highest penetrance for PD and it is also observed that α-synuclein accumulates to form Lewy bodies in affected DA neurons. On the other hand, GBA1 is the most common mutation linked to PD with about 5-8% of PD patients having mutation in the GBA1 gene. GBA1 encodes the enzyme Glucocerebrosidase (GCase) which is required for the catabolism of glucosylceramide and glucosylsphingosine, which when mutated, results in lipid accumulation in the affected cells. Mutations to SNCA and GBA1, therefore, lead to accumulation of cellular substrates but the link between SNCA, GBA1 and PD remains elusive.
In our lab, we are refining a pipeline to systematically assess the link between α-synuclein and GCase in PD. In a collaboration with the Department of Biosystem Science and Engineering of the ETH Zurich, we are assessing the electrophysiological patterns and defects of midbrain floorplate DA neurons generated from PD patient-derived human induced pluripotent stem cells (iPSCs) with state-of-the-art high density microelectrode arrays (HDMEAs). The aim is to develop a functional screen in order to identify pharmacological agents to rescue DA neurons in PD.