Is the solution for Parkinson’s right in front of our nose?
Most people are unaware that a diminished sense of smell is one of the first signs of Parkinson’s disease. Long before the characteristic movement symptoms occur, more than 95% of Parkinson’s disease patients experience an impaired ability to detect odours. By the time movement symptoms become apparent and a diagnosis can be made, the neurons in an area of the brain that controls movement have been decimated, strangled by toxic clumps of a protein called alpha synuclein. The time frame between olfactory symptoms and the typical movement symptoms has captured our attention as a potential window to intervene in the disease.
At the University of Auckland, Centre for Brain Research, we’ve become increasingly interested in understanding the changes happening in the brain within this symptom window. Our recently released paper (https://www.nature.com/articles/s41598-020-63412-x) published in Nature-Scientific Reports presents new findings that toxic alpha synuclein clumps build up within many different types of cells within the human olfactory bulb, the tiny organ that forms the gateway between the brain and the outside world through our nose. By studying olfactory bulbs from post-mortem donated brains, we have shown that alongside the neurons affected by alpha synuclein accumulation there are other types of brain cells — immune cells and cells associated with blood vessels — that are also affected. These findings highlight for the first time the potential role of non-neuronal supporting cells in the earliest stages of Parkinson’s disease.
The pathway of alpha synuclein
Alpha synuclein accumulation is the hallmark feature of Parkinson’s disease pathology, but its exact mechanism of toxicity continues to elude us. A wealth of evidence shows that these alpha synuclein clumps contribute to neuronal dysfunction and degeneration. A major clue may lie in the distinct patterned spread of these toxic clumps: post-mortem studies of brains from Parkinson’s disease patients show that alpha synuclein accumulates within specific brain regions and progresses from one area to another as the disease progresses. This spread of alpha synuclein between connected brain regions has also been demonstrated in animal models and targeting this process is a promising opportunity to slow the disease progression. Three years ago, we were the first to discover that alpha synuclein can move between human brain cells through connections called nanotubes (https://www.nature.com/articles/srep42984). Transfer through nanotubes allows the alpha synuclein to pass between cells undetected by the immune cells that survey the brain. If Parkinson’s disease begins from the nose, then this may be how it spreads to deeper brain regions.
New potential routes for alpha synuclein to spread around the brain
In our current study we explored whether olfactory bulb cells other than neurons were affected by alpha synuclein clumps, as these supporting cell types could also have a crucial role to play in the spread of alpha synuclein. We screened thousands of cells from different Parkinson’s disease olfactory bulbs and found both neurons and a range of supporting cells with diverse functions contained the toxic clumps. Unsurprisingly, we found alpha synuclein within astrocytes, which are star-shaped cells that support neuronal function and regulate the blood-brain barrier. Astrocytes are the most numerous type of cell in the brain and have been widely implicated in Parkinson’s disease pathology in other brain regions. One of our most novel findings is that a similar number of pericytes also contain alpha synuclein. Pericytes are not as abundant as astrocytes, but they are essential cells that regulate blood flow, permeability of the blood-brain barrier and contribute to the brain’s inflammatory response. Their proximity to brain vasculature suggests the potential for alpha synuclein to migrate through the blood vessel system. Lastly, we found alpha synuclein within microglia, the immune sentinels that can orchestrate a potent inflammatory response and clean up debris like alpha synuclein clumps. We didn’t observe any alpha synuclein within oligodendrocytes which function to support and insulate neuronal connections. This specificity in the olfactory bulb cell types affected by the toxic build-up of alpha synuclein allows us to pin-point which cells are most-likely responsible for transmitting it to other brain regions.
A window to delay the disease onset
Armed with this new knowledge that different types of cells contain alpha synuclein clumps within one of the earliest symptom regions, we now have several promising targets to pursue. Our aim is to delay the spread of alpha synuclein and the disease onset. If successful and we can defer onset by 5 years, it could reduce the number people in our society suffering from Parkinson’s disease by 50%. With promising evidence suggesting the olfactory system could be a starting point of the disease pathology, we believe that the key to preventing Parkinson’s disease is right in front of our nose.
This article was written by Dr and Dr Victor Dieriks. We would like to thank the other people involved, because without them this work would not have been possible; Taylor Stevenson, Clinton Turner, Prof Richard Faull, Prof. Maurice Curtis, Brain Bank staff, funders and most importanty the families and donors of human brain tissue who make our research possible.
