Researchers at the University of Pittsburgh (PA, USA) led by J. Timothy Greenamyre (University of Pittsburgh ) appear to have elucidated the mechanism by which alpha-synuclein causes neurotoxicity in Parkinson’s disease (PD) brains. The findings were published recently in Science Translational Medicine.
PD is a progressive neurodegenerative disease with motor symptoms including tremor, rigidity, bradykinesia and postural instability. A key pathological feature of PD is the selective loss of dopaminergic neurons in the brain, accompanied by the formation of alpha-synuclein rich Lewy body protein aggregates. High levels of alpha-synuclein have also been linked to the disruption of normal mitochondrial functioning, however the relationship between these two entities has remained unclear.
The Pittsburgh Institute for Neurodegenerative Diseases (PIND), directed by Greenamyre, is a collaborative approach that aims to study the mechanisms of various neurodegenerative diseases and produce novel therapies and diagnostics for patients suffering from these diseases.
“With four different PIND investigators working together, the new study highlights the power of this collaborative approach,” Dr. Greenamyre added.
Utilizing a rodent model of PD, Greenamyre and his team have demonstrated that alpha-synuclein disrupts mitochondrial function through attachment to the TOM20 mitochondrial protein. This prevents optimal mitochondrial function and results in a reduced level of energy production and increased amount of damaging cellular waste; ultimately causing neurodegeneration. These findings were also later confirmed in PD patient brain tissue.
“The effects of alpha-synuclein on mitochondria are like making a perfectly good coal-fuelled power plant extremely inefficient, so it not only fails to make enough electricity, but also creates too much toxic pollution,” stated Greenamyre.
The research team also demonstrated in cell cultures, two ways by which alpha-synuclein induced toxicity could be prevented. The first technique involved utilizing gene therapy to cause neurons to produce higher levels of TOM20 protein, which provided a neuroprotective effect from alpha-synuclein. The second technique employed a protein that prevented alpha-synuclein from attaching to TOM20, thus reducing the harmful effects to the mitochondria.
Current treatments for PD are merely symptom based and do not slow disease progression. While further research is required to translate these suggested techniques to the clinic, Greenamyre is confident that this initial research carried out at the PIND will lead to human clinical trials in the future.
Sources: www.upmc.com/media/NewsReleases/2016/Pages/greenamyre.aspx; Di Maio, P. J. Barrett, E. K. Hoffman et al. α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci. Transl. Med. 8 (342), 342ra78 (2016).