Aligning Science Across Parkinson’s

In a notable continuation of its journey to unravel Parkinson’s disease (PD), a team led by Wade Harper, PhD, the Bert and Natalie Vallee Professor of Molecular Pathology and chair of the Department of Cell Biology in the Blavatnik Institute at Harvard Medical School, has received an additional $5.25 million from the Aligning Science Across Parkinson’s (ASAP) initiative. These funds will support the team’s work within the Collaborative Research Network (CRN), an international, multidisciplinary group of investigators aiming to address key gaps in understanding the basic mechanisms driving PD’s development and progression.

The Michael J. Fox Foundation, ASAP’s implementation partner, issued the grant, which will propel research into the molecular and cellular aspects of early-stage PD. Building on an initial $7.2 million grant from ASAP, Team Harper—including co-investigators Ruben Fernandez-Busnadiego, PhD (University of Göttingen); Judith Frydman, PhD (Stanford University); Franz-Ulrich Hartl, MD (Max Planck Institute of Biochemistry [MPIB]); Brenda Schulman, PhD (MPIB); and Florian Wilfling, PhD (Max Planck Institute of Biophysics)—is dedicated to investigating how disruptions in cellular quality control contribute to PD.

The team is intensifying its efforts to understand how aging contributes to loss of quality control pathways in the context of cells harboring genetic risk factors for Parkinson’s disease. “Our most challenging task is elucidating the molecular mechanisms of genes that normally function in protein and organelle quality control pathways linked to PD,” Harper says. “Several Parkinson’s risk genes function in pathways that are important for clearance of aberrant proteins and organelles, and understanding how these pathways are defective in disease requires a multifaceted approach.”

Using advanced methods such as cryo-electron tomography (cryo-ET) for visualizing proteins and organelles at nanometer resolution and proteomics to uncover defective pathways, the team maps how genetic risk factors and aging converge to impact cellular processes, thereby highlighting their influence on PD progression.

Ekemini A. U. Riley, PhD, ASAP’s managing director, underscores the team's contributions to the CRN and PD research field. “Team Harper has made substantive progress in broadening our knowledge of the mechanisms that impact cellular quality control and their relation to Parkinson’s disease, while exemplifying ASAP’s collaborative nature and open science principles,” she says. “We hope that the research carried out by Team Harper and other CRN teams will bring new ideas to the field, which may one day lead to new avenues of investigation for PD.”

The Harper team’s use of cryo-ET provides unprecedented insights into cellular structures, offering new perspectives on PD at the molecular level. “This approach generates new hypotheses about which defects might be relevant to the disease,” Harper shares, emphasizing its role in revealing how protein clumps (called Lewy bodies) associated with PD alter cellular pathways and contribute to neurodegeneration.

Furthermore, the team is enhancing proteomic techniques to better understand the molecular dynamics of Parkinson’s risk genes, aiming to identify critical cellular functions disrupted by protein clumps, potentially uncovering new therapeutic avenues.

The supplemental funding will also allow the team to explore novel interactions within the endolysosomal system, a pathway that includes several proteins that are defective in familiar forms of Parkinson’s disease. This is crucial for understanding how PD-linked protein aggregates like α-synuclein, which clump in certain brain disorders, impact disease progression. Harper notes, “Understanding α-synuclein toxicity at the molecular level will suggest strategies to protect cells from its harmful effects.”