Novel treatment target could revolutionise Parkinson's therapy

Parkinson’s disease is a chronic degenerative neurological disorder that is characterised by the gradual loss of neurons from the basal ganglia, an area of the brain that deals with voluntary movement, procedural learning and routine behaviours. Over time, symptoms such as tremor, hypokinesia and gait abnormality develop which progressively worsen as the disease advances, eventually leading to death. Parkinson’s was first described by James Parkinson, where the disease takes its name, in his 1817 article An Essay on the Shaking Palsy, and now affects 6.2 million people worldwide resulting in 117,400 deaths annually.

As the neurons affected use dopamine as their neurotransmitter, current therapies have aimed to increase the level of dopamine in the basal ganglia, thus compensating for neuronal loss. L-3,4-Dihydroxyphenylalanine (L-DOPA) is the main Parkinson’s treatment, with the majority of sufferers taking it at some point. Due to the non-specific nature of L-DOPA, other areas of the brain and peripheral nervous system can be affected by increased levels of dopamine, causing psychological effects similar to schizophrenia. L-DOPA and any other treatments only work to slow disease progression, becoming less effective as the disease advances, highlighting the need for more concrete treatments, or even cures, to be researched and developed.

A study from the University of Guelph, published in Nature Communications, has found that cardiolipin, an important component of the inner mitochondrial membrane, ensures the correct folding of the protein α-synuclein. Misfolded α-synuclein is a major constituent of Lewy bodies, abnormal protein aggregates that develop inside neurons leading to their decline in function and eventual necrosis. Previous studies have shown that mutant SNCA, the gene that encodes α-synuclein, is associated with early-onset Parkinson’s and has accelerated β-pleated sheet formation (misfolding) and fibrilisation of α-synuclein when compared to the wild-type, leading to the formation of Lewy bodies. Interactions between α-synuclein and the mitochondrial membrane promote the adoption of α-helical structures which are unable to form Lewy bodies or fibrilise, reducing neuronal loss.

 

 

Currently there are no treatments that stop nerve cells from dying"

Professor Scott Ryan, senior study author

"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." Professor Scott Ryan, senior study author.

The team used human pluripotent stem cells to model Parkinson’s disease, comparing cells that express a mutant SNCA gene with controls. They found that cardiolipin moves to the outer mitochondrial membrane where it interacts with α-synuclein, folding it into an α-helical conformation. In SNCA mutants, this process is slowed, increasing the level of misfolded α-synuclein on the mitochondrial membrane. This leads to a significant increase in the recruitment of LC3, a protein that promotes autophagy of the mitochondria, causing mitochondrial stress and eventual cell death.

"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." Scott Ryan

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.", said Ryan.