Keep Calm and Research On
Even in a landscape of uncertainty, we are ‘unbroken’ and we have hope.
Thanks to the travel support from the WPC, I was able to attend and present my work at the 5th World Parkinson Congress in Kyoto, Japan, which left me with a whirlwind of memories. Despite geographic distance, cultural differences and language barriers, for four full days, there were so many inspirational moments, meaningful and insightful discussions between Parkinson’s Disease patients, neurologists, researchers, care partners, sponsors and exhibitors. In addition, WPC incorporated a host of wellness activities, art and performances inspired by Parkinson’s, everything from painting, poetry through to origami and quilting that informed, educated, expressed and inspired.
As a basic scientist, my research is definitely enriched by the insights provided by the patients and those who care for them at a conference such as WPC. Despite the overall richness of the whole meeting, there was a high level of basic science sessions at the 2019 WPC. It was a valuable opportunity to learn the latest information in the field, disseminate the lab group’s most current research data, to be inspired and network with potential collaborators.
I presented a poster entitled "Parkinson’s disease-linked D620N VPS35 knockin mice manifest tau neuropathology and dopaminergic neurodegeneration" with findings from my recent publication examining how mutations in the VPS35 gene could contribute to the development of Parkinson’s disease (PD). It was a privilege to be invited to be part of the Poster Tour program which allowed me to further discuss my Parkinson's Foundation-supported research with other delegates.
Over the past 20 years, researchers have identified rare mutations in genes that can directly cause Parkinson’s disease (PD) or increase the risk of developing the disease. VPS35 mutations represent the second most common cause of late-onset inherited PD after LRRK2 mutations and give rise to a disease spectrum with clinical symptoms and neuroimaging phenotypes similar to sporadic PD. Like a sorting machine in an assembly line, a major part of what VPS35 does is to recycle normal cargo proteins to prevent their degradation for neuronal survival. However, it is not yet clear how they could contribute to the development of PD. The neuropathological spectrum of PD brains harboring VPS35 mutations is not yet clear since only a single mutation carrier has so far been evaluated at autopsy. Unfortunately, this evaluation lacked an assessment of brain regions of interest, including substantia nigra where dopamine-producing nerve cells are lost and αSyn accumulates abnormally into clumps, called Lewy bodies in PD. There are some promising drugs in development that target LRRK2 but none that target VPS35. Development of appropriate animal models for PD is critical for the identification of potential targets for the treatment and prevention of PD. Most prior research has focused on model systems that lack the gene or overexpress mutant human variants of VPS35. We employed a highly relevant and new mouse model (VPS35 KI) that expresses normal amounts of mouse VPS35, but it is mutated so that the protein does not function properly. We provide evidence that the PD-causing D620N mutation is sufficient to reproduce neuropathological hallmarks of PD as indicated by an age-dependent loss of dopamine-producing nerve cells and widespread axonal pathology. Furthermore, VPS35 KI mice exhibit dysfunctional microtubule-associated protein tau with advancing age but lack signs of Lewy pathology positive for αSyn. The buildup of defective proteins in neurons is a feature shared by PD and several other neurodegenerative conditions. Tau is one of the major proteins to amass in the brain and cause damage in these diseases, creating a condition described as tauopathy. Importantly, tau pathology can occur in familial and sporadic PD brains albeit much less prominently than Lewy pathology.
Researchers have recently demonstrated that abnormal interaction between proteins implicated could lead to genetic changes that are found in people with PD. Thus we want to understand whether and how mutated VPS35 might cooperate with either αSyn or tau to harm dopamine neurons in PD. Understanding their interactions could help develop new drugs that interfere with the actions of these proteins to prevent or treat PD. We find that D620N VPS35 expression does not induce αSyn neuropathology and has no effect on the αSyn-induced phenotypes that develop in PD model mice. Therefore, D620N VPS35 KI mice do not have an obvious pathological interaction with αSyn. VPS35 and tau could be important for the pathophysiology of PD and have a functional relationship that implicates both proteins in a common pathogenic pathway. How VPS35 mutations induce tau pathology is not known and the significance of tau pathology for driving neurodegenerative processes in VPS35-linked PD is largely unexplored.
Since the WPC ended nine months ago, I have been focusing on the relationship between VPS35 mutations and tau pathology, including the mechanism for inducing tau abnormalities and whether tau itself is important for dopaminergic neurodegeneration in the D620N VPS35 KI mice. I have conducted parallel studies using viral-mediated gene transfer models to explore the role of D620N VPS35 mutation on mutant tau-induced neurodegeneration and the neuron-to-neuron transmission of human WT-tau within the mouse hippocampus. We are in the process of completing the studies for publication in the near future.
I have been privileged to be able to go to WPC in Kyoto and would strongly encourage others to go. It’s an incredible opportunity that can only help move things forward for the PD community.
Abstracts from the WPC 2019, WPC 2016, and WPC 2013 are still downloadable on the WPC website.
Xi Chen, PhD, is a research scientist, Laboratory of Molecular Neurodegeneration (The Moore Laboratory), Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI.
This research was shared as an abstract at the WPC 2019 in Kyoto. WPC is pleased to support abstracts authors by sharing their ongoing work. WPC abstract books can be downloaded from the past three Congresses HERE.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions of the World Parkinson Coalition®