Insights into the cause of cell death in Parkinson's

Insights into the cause of cell death in Parkinson's

Researchers have discovered one of the factors behind nerve cell death in Parkinson's disease, unlocking the potential for treatment to slow the progression of this fatal neurodegenerative disorder.

They found that cardiolipin, a molecule inside nerve cells, helps ensure that a protein called alpha-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 development of therapies against Parkinson's disease," said the senior author. "Currently there are no treatments that stop nerve cells from dying."

Published in the journal Nature Communications, the study used stem cells collected from people with the disease. The research team studied how nerve cells try to cope with misfolded alpha-synuclein.

"We thought if we can better understand how cells normally fold alpha-synuclein, we may be able to exploit that process to dissolve these aggregates and slow the spread of the disease," senior author said.

The study revealed that, inside cells, alpha-synuclein binds to mitochondrial membrane, where cardiolipin resides. Cells use mitochondria to generate energy and drive metabolism. Authors show in stem cells that α-syn -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,

Normally, cardiolipin in mitochondria pulls synuclein out of toxic protein deposits and refolds it into a non-toxic shape.  Prolonged cardiolipin exposure in α-syn -mutants initiates recruitment of LC3 to the mitochondria and mitophagy.  The researchers found that, in people with Parkinson's disease, this process is overwhelmed over time and mitochondria are ultimately destroyed, said the senior author.

"As a result, the cells slowly die. 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."

Authors  also show that co-culture of SNCA-mutant neurons with their isogenic controls results in transmission of α-syn pathology coincident with mitochondrial pathology in control neurons.