Cardiolipin May Be New Target For Therapies Against Parkinson’s Disease

One of the factors behind nerve cell death in Parkinson’s disease has been revealed by a researcher at University of Guelph. His finding unlocks the potential for treatment to slow the progression of this fatal neurodegenerative disorder.

Prof. Scott Ryan has 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.

Cardiolipin Exposure

Parkinson’s disease is the most common degenerative movement disorder in Canada, affecting about 100,000 people. Ryan, a professor in U of G’s Department of Molecular and Cellular Biology, said:

“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. Currently there are no treatments that stop nerve cells from dying.”

The study used stem cells collected from people with the disease. Ryan’s 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,”

he said.

Misfolded Alpha-synuclein

The study revealed that, inside cells, alpha-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 non-toxic shape.

α-Syn mutant hNs acquire early signs of α-syn pathology.

α-Syn mutant hNs acquire early signs of α-syn pathology.
a, b Accumulation of insoluble Ubq/α-syn PS129 protein in hiPSC-derived A53T and corrected hNs (a) or hESC-derived WT, A53T and E46K hNs
(b) was determined by TX-100 wash-out of soluble protein prior to fixation. DIV: 60. Scale bar: 10 µm.
(c, d) Fluorescence resonance energy transfer (FRET) from Alexa-488-labeled ubiquitin to Alexa-594-labeled α-syn PS129 in hiPSC-derived A53T and corrected hNs or hESC-derived WT, A53T and E46K hNs was assessed and mean FRET intensity was quantified
(d). Data represent mean ± s.e.m. **P < 0.01 by ANOVA followed by Tukey’s post hoc test, n = 6 coverslips over three independent differentiations, DIV: 60 or 90. Scale bar: 50 µm
Credit: Tammy Ryan et al, CC-BY.

The U of G researchers found that, in people with Parkinson’s disease, this process is overwhelmed over time and mitochondria are ultimately destroyed, said Ryan;

“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.”

He said understanding cardiolipin’s role in protein refolding may help in creating a drug or therapy to slow progression of the disease.

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

he concludes.

The work was supported in part by the Parkinson Society of Canada, the Natural Sciences and Engineering Research Council of Canada, the CRC Program, and NIH grants.

Tammy Ryan, Vladimir V. Bamm, Morgan G. Stykel, Carla L. Coackley, Kayla M. Humphries, Rhiannon Jamieson-Williams, Rajesh Ambasudhan, Dick D. Mosser, Stuart A. Lipton, George Harauz & Scott D. Ryan
Cardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein
Nature Communications volume 9, Article number: 817 (2018) doi:10.1038/s41467-018-03241-9

Top Image: Tammy Ryan et al, CC-BY.