Parkinson's Neuronal Loss Linked to Mitochondrial Membrane Lipid

Understanding the underlying molecular mechanisms that mediate the deterioration of cellular function is a critical factor for any disease, and with our incomplete knowledge of neurobiology, it’s essential. If we hope to develop improved therapeutics to slow or even stop the progression of fatal neurodegenerative disorders like Parkinson’s disease, then identifying the cellular pathways that lead to neuronal loss is crucial.

Now, a new study from investigators at the University of Guelph, Ontario, has uncovered what they believe is a main factor behind nerve cell death in Parkinson’s disease. The findings from the new study were published online today in Nature Communications, in an article entitled “Cardiolipin Exposure on the Outer Mitochondrial Membrane Modulates α-Synuclein.”

The Canadian researchers found that cardiolipin – a lipid molecule found in the mitochondrial membrane – helps ensure that a protein called α-synuclein folds properly. Misfolding of this protein leads to protein deposits that are the hallmark of Parkinson’s disease. These deposits are toxic to nerve cells that control voluntary movement. When too many of these deposits accumulate, nerve cells die.

“Identifying the crucial role cardiolipin plays in keeping these proteins functional means cardiolipin may represent a new target for the development of therapies against Parkinson’s disease,” explained Scott Ryan, Ph.D., a professor in the department of molecular and cellular biology at the University of Guelph. “Currently there are no treatments that stop nerve cells from dying.”

In this new study, the investigators used stem cells collected from people with the disease. The research team studied how nerve cells try to cope with misfolded α-synuclein.

“Using human pluripotent stem cells (hPSCs) that allow comparison of cells expressing mutant SNCA (encoding α-synuclein (α-syn)) with isogenic controls or SNCA-transgenic mice, we showed that SNCA-mutant neurons display fragmented mitochondria and accumulate α-syn deposits that cluster to mitochondrial membranes in response to exposure of cardiolipin on the mitochondrial surface,” the authors wrote. “Whereas exposed cardiolipin specifically binds to and facilitates refolding of α-syn fibrils, prolonged cardiolipin exposure in SNCA-mutants initiates recruitment of LC3 to the mitochondria and mitophagy.”

“We thought if we can better understand how cells normally fold α-synuclein, we may be able to exploit that process to dissolve these aggregates and slow the spread of the disease,” Dr. Ryan added.

The study revealed that, inside cells, α-synuclein binds to mitochondria, where cardiolipin resides. Cells use mitochondria to generate energy and drive metabolism. Normally, cardiolipin in mitochondria pulls synuclein out of toxic protein deposits and refolds it into a nontoxic shape.

Interestingly, the research team found that, in people with Parkinson’s disease, this process is overwhelmed over time and mitochondria are ultimately destroyed.

“As a result, the cells slowly die,” Dr. Ryan remarked. “Based on this finding, we now have a better understanding of why nerve cells die in Parkinson’s disease and how we might be able to intervene.”

Amazingly, the authors also found that “co-culture of SNCA-mutant neurons with their isogenic controls results in the transmission of α-syn pathology coincident with mitochondrial pathology in control neurons. Transmission of pathology is effectively blocked using an anti-α-syn monoclonal antibody (mAb), consistent with cell-to-cell seeding of α-syn.”

Understanding cardiolipin’s role in protein refolding helps provide the foundation blocks for building potential new therapies to slow progression of Parkinson’s disease.

“The hope is that we will be able to rescue locomotor deficits in an animal model. It’s a big step toward treating the cause of this disease,” Dr. Ryan concluded.