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.
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.
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.
Below is an example of a research output from the team that contributes to the ASAP mission of accelerating discoveries for PD.
Quantitative proteomics reveals the selectivity of ubiquitin-binding autophagy receptors in the turnover of damaged lysosomes by lysophagy
Lysosomes are critical for the turnover of damaged organelles and possibly protein aggregates via autophagy, but there is also evidence that lysosomes can become damaged during aging or in the context of particular disease mutations. Proteomic analyses of changes occurring during lysophagy identified TAX1BP1 as a central component in the pathway. In addition to identifying a new upstream target that controls lysophagy, this study provides a proteomic resource for future studies focused on lysophagy.
Other Team Activities
- Protocol Particulars Interview with Cristina Capitanio
- 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.