Reduced Neuroplasticity Precedes Neurodegeneration in Parkinson s Disease Patient-Specific Midbrain Organoids
Abstract
Parkinsonism refers to a group of movement abnormalities such as bradykinesia, muscle rigidity, postural instability, and resting tremors. Parkinson s disease (PD) is the most common cause of Parkinsonism, which is also coupled with several non-motor symptoms including depression, constipation, sleep disturbances, hypertension, and even dementia in advanced disease stages. The disease is the second most common neurodegenerative disorder after Alzheimer s disease and is prevalent mainly in the aged population. PD currently affects around one million Americans and every year 60,000 people in the U.S. alone are diagnosed with PD. There are both genetic and environmental risk factors identified to cause PD. While only 5% to 10% of PD patients carry one or more of the known genetic risk factors, the others are believed to have acquired the disease because of exposure to hazardous chemicals or fumes [1]. It is noteworthy here, that Veterans are highly susceptible to acquiring PD and an epidemiology study showed a 2.1-fold increased risk of PD among men who were deployed to World War II [2]. In addition to the above, the disease imposes a huge economic burden to the individual and to society because of the lack of treatment. While treatment addressing individual symptoms exists and provides temporary relief to patients, there is so far no medication in the market to effectively slow down or cure Parkinson s disease. Thus, in the current state, the recurrent direct costs per patient sums up to USD$22,800 per year [3]. Despite the growing necessity to find a treatment strategy for curing the disease, there exists none so far because of the limited knowledge of the disease mechanism. Research in neurodegenerative diseases such as PD is hindered by the lack of an accurate model to mimic the disease for experimentation. The widely used animal models such as mouse and fish do not recapitulate PD accurately. In this project, we propose the use of patient skin cells derived induced pluripotent stem cells (iPSCs) to generate midbrain organoids and use these to demonstrate the disease manifestation of PD. Organoids (in vitro miniature of organs) are 3D cultures of cells that self-organize spatially to replicate the organ they are directed to be. The advantage of using this as a model is that these are human cell-derived and hence closely recapitulate human diseases like PD, are personalized to the individual, and can be generated reliably in large amounts for high-throughput experiments, which are also relevant for drug screening. Using these midbrain organoids, we aim to understand how reduced neuroplasticity can cause neurodegeneration. Although there are sufficient logical indications that neuroplasticity precedes neurodegeneration, there is no experimental evidence for this, which would allow dissecting the mechanism on how this happens. In the course of this project, we aim to uncover the underlying mechanisms of neuroplasticity and neurodegeneration and identify targets for early diagnosis and therapeutic interventions. Since our results will be obtained from experiments on different patient-derived organoid cultures having both idiopathic (unknown cause) and mutation-driven PD, we expect the results to be applicable to a significantly large number of patients. Indeed, once the experiments from this project are established, they can be replicated with samples from other patients. This makes our approach amenable to personalized experiments. In summary, the foremost outcome of this project will expand the understanding on how the mechanisms of neuroplasticity causes PD. Our experiments will further identify compounds and targets to rescue the disease manifestation. Moreover, we believe that the identified targets at the end of this work would be easily translatable for clinical application because the results are derived from human-derived cells. Lastly, it would leverage the use of midbrain organoids as a model
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810812
Entities
People
- Jens Schwamborn
Organizations
- United States Army
- University of Luxembourg