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HEAT-Net 2021 | Alpha-synuclein pathology: dangerous mitochondrial interactions

Alpha-synuclein tends to misfold and aggregate in patients with progressive Parkinson’s Disease, Dementia with Lewy bodies, multiple system atrophy, and other neurodegenerative conditions. Tiago Outeiro, PhD, University Medical Center Göttingen, Göttingen, Germany, describes the presence of high levels of alpha-synuclein in the synaptic compartment and how it affects synaptic function by influencing the release of neurotransmitters. Prof. Outeiro discusses the use of super-resolution microscopy techniques to image the synaptic compartment and specifically the interactions of alpha-synuclein with other proteins. By utilizing proteomics, a recent study has demonstrated some of the dangerous interactions of alpha-synuclein with mitochondrial proteins; proteins were being retained in the cytosol rather than being directed into the mitochondria, thus leading to mitochondrial dysfunction. This interview took place at the Harvard European Alumni Training Network (HEAT-Net), 2021.

Transcript (edited for clarity)

Alpha-synuclein is a key player in Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, and perhaps even other neurodegenerative diseases, because it accumulates as misfolded species in the brains of the patients as they age and as disease progresses. We know that this protein exists in high amounts in the synaptic compartment, and we know from the work of many colleagues in the field that it seems to influence synaptic function by interfering with the release of synaptic vesicles...

Alpha-synuclein is a key player in Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, and perhaps even other neurodegenerative diseases, because it accumulates as misfolded species in the brains of the patients as they age and as disease progresses. We know that this protein exists in high amounts in the synaptic compartment, and we know from the work of many colleagues in the field that it seems to influence synaptic function by interfering with the release of synaptic vesicles.

So here in my talk, it’s a short talk, so we’ll not be able to cover everything we do in detail, but what I’ll try to do is to really highlight some of our most recent work where we are trying to use super resolution microscopy techniques to image alpha-synuclein in the synaptic compartment, to image its interactions with other proteins, and we think this might be relevant in the context of the biology, but also of the pathobiology of alpha-synuclein. And I will touch on a study that we did recently, where we used proteomics to find interactors, and we found that some of these dangerous interactions could be with mitochondrial proteins that should normally be going into the mitochondria, and because alpha-synuclein may be interacting with them, they are kept in the cytosol and will not play their role where they should be playing in the mitochondria and so this may compromise mitochondrial function. So in a nutshell, this is what I’ll try to do in my presentation.

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