PD Functional Genomics | 2020
Mechanisms Overwhelming Protein and Organelle Quality Control in Parkinson’s Disease
Study Rationale: Abnormal protein aggregation and prion-like aggregate spreading are hallmarks of the degenerative cascades of sporadic and familial Parkinson’s disease (PD) and can damage cells, including neurons. Multiple mechanisms of aggregate toxicity have been implicated in cellular PD pathology, and PD risk alleles may have the potential to illuminate additional underlying biological mechanisms.
Hypothesis: Parkinson’s disease, at the molecular level, results from the failure of cellular quality control (QC) mechanisms, and finding ways to maintain (or augment) QC capacity will provide new therapeutic strategies for PD and possibly other neurodegenerative disorders.
Study Design: Using powerful molecular visualization and discovery tools in disease-relevant cells, Team Harper will elucidate how individual types of protein aggregates linked with PD strains (including patient-derived aggregates) alter cellular pathways, including effects on cell survival and function. Team Harper will also use genetic approaches to understand what cellular proteins promote the processing of PD-related aggregates.
Impact on Diagnosis/Treatment of Parkinson’s Disease: Team Harper’s expectation is that this work will identify those critical cellular functions that are disrupted by protein aggregates and will help define how mutations alter the underlying mechanisms of dysfunctional proteostasis.
Leadership
Project Outcomes
Through biochemical reconstitution, in situ structural analysis, and genetic perturbations, this project will directly visualize pathogenic mechanisms in cells and in reconstituted systems at nanometer and subnanometer resolution, providing an unprecedented understanding of how a-synuclein strains and other PD mutants promote cellular dysfunction. View Team Outcomes.
Team Outputs
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Overall Contributions
Here is an overview of how this team’s article findings have contributed to the PD field as of November 2023. There are two different categorizations of these contributions – one by impact to the PD community and a second by scientific theme.
Impact
Theme
Featured Output
Below is an example of a research output from the team that contributes to the ASAP mission of accelerating discoveries for PD.
Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways
A hallmark of neurodegenerative diseases such as Parkinson’s disease is the progressive loss of proteostasis, leading to the conversion of proteins from productive folding pathways to populate aggregation-prone misfolded (non-native or intermediate) states. To combat this toxicity, cells have evolved degradation pathways (ubiquitin-proteasome system and autophagy) that detect and degrade misfolded proteins. Here, the authors find that aggregation burden dictates the activation of proteasome-dependent quality control pathways. Initial misfolded proteins, enriched in oligomers, utilize UBE3C-dependent proteasomal degradation, while higher aggregation levels, enriched in larger insoluble structures, activate the NRF1 transcription factor to increase the proteasome subunit transcription and subsequent degradation capacity of cells. The role of UBE3C and NRF1 in aggregation clearance may provide therapeutic targets to prevent neurodegenerative disease.
Team Accolades
Members of the team have been recognized for their contributions.
- Open Science Champions: Felix Kraus, Harper Lab, Cristina Capitanio
- Network Spotlights: Felix Kraus
- Awards
- 2023 Collaborative Meeting: Cole Sitron (Community Poster Award Winner; London)
Other Team Activities
- Protocol Particulars Interview: iNeuron Differentiation on EM Grids with Cristina Capitanio, MSc
- Interest Groups:
- Mitochondrial Pathways – J. Wade Harper (Past Chair)
- Endolysosomal Pathways – J. Wade Harper (Chair)
In the News
- Check back soon for updates from Team Harper.
