Parkinson's Protein Transition Provides Insight into Disease Progression

Researchers say they have completed a detailed brain cell analysis that has helped them to uncover new mechanisms thought to underlie Parkinson’s disease. They believe their study (“α-Synuclein Oligomers Interact with ATP Synthase and Open the Permeability Transition Pore in Parkinson’s Disease”), published in Nature Communications, adds to the growing understanding of the causes of Parkinson’s and other neurodegenerative diseases and could influence drug design in the future.

“Protein aggregation causes α-synuclein to switch from its physiological role to a pathological toxic gain of function. Under physiological conditions, monomeric α-synuclein improves ATP synthase efficiency. Here, we report that aggregation of monomers generates beta sheet-rich oligomers that localise to the mitochondria in close proximity to several mitochondrial proteins including ATP synthase. Oligomeric α-synuclein impairs complex I-dependent respiration. Oligomers induce selective oxidation of the ATP synthase beta subunit and mitochondrial lipid peroxidation. These oxidation events increase the probability of permeability transition pore (PTP) opening, triggering mitochondrial swelling, and ultimately cell death,” write the investigators.

“Notably, inhibition of oligomer-induced oxidation prevents the pathological induction of PTP. Inducible pluripotent stem cells (iPSC)-derived neurons bearing SNCA triplication, generate α-synuclein aggregates that interact with the ATP synthase and induce PTP opening, leading to neuronal death. This study shows how the transition of α-synuclein from its monomeric to oligomeric structure alters its functional consequences in Parkinson’s disease.”

For years, scientists have known that Parkinson’s is associated with a buildup of α-synuclein protein inside brain cells. But how these protein clumps cause neurons to die was a mystery. Using a combination of detailed cellular and molecular approaches to compare healthy and clumped forms of α-synuclein, a team of scientists at the Francis Crick Institute, UCL, UK Dementia Research Institute at the universities of Cambridge and Edinburgh, New York University, and other collaborators have discovered how the protein clumps are toxic to neurons.

They found that clumps of α-synuclein moved to and damaged key proteins on the surface of mitochondria, making them less efficient at producing energy. They also triggered a channel on the surface of mitochondria to open, causing them to swell and burst, leaking out chemicals that tell the cell to die.

These findings were replicated in human brain cells generated from skin cells of patients with a mutation in the α-synuclein gene, which causes early-onset Parkinson’s disease. By turning patient skin cells into stem cells, they could chemically guide them into become brain cells that could be studied in the lab. This technique provides a valuable insight into the earliest stages of neurodegeneration, something that brain scans and postmortem analysis cannot capture, according to Sonia Gandhi, Ph.D., group leader at the Crick and UCL, and joint senior author of the study.

“Our findings give us huge insight into why protein clumping is so damaging in Parkinson’s and highlight the need to develop therapies against the toxic form of α-synuclein, not the healthy nonclumped form,” she explained.

“This study was a complex collaboration at the interface of chemistry, biophysics, and biology, bringing scientists from different disciplines together to investigate a longstanding problem in Parkinson’s research,” added Andrey Abramov, Ph.D., co-investigator at UCL and joint senior author of the paper.