Is Axonal Degeneration a Key Early Event in Parkinson’s Disease?

Abstract

Recent research suggests that in Parkinson's disease the long, thin and unmyelinated axons of dopaminergic neurons degenerate early in the disease process. We organized a workshop entitled 'Axonal Pathology in Parkinson's disease', on March 23 rd , 2016, in Cleveland, Ohio with the goals of summarizing the state-of-the-art and defining key gaps in knowledge. A group of eight research leaders discussed new developments in clinical pathology, functional imaging, animal models, and mechanisms of degeneration including neuroinflammation, autophagy and axonal transport deficits. While the workshop focused on PD, comparisons were made to other neurological conditions where axonal degeneration is well recognized. Main textAround 7 -10 million people worldwide suffer from Parkinson's disease (PD). PD is usually diagnosed based on motor symptoms (e.g. tremor, slowness of movements, bradykinesia) which are attributed to loss of dopamine in the striatum, as a consequence to degeneration of nigrostriatal dopamine neurons. Devising methods to protect the cell bodies of nigral dopamine neurons has long been a research priority, but emerging knowledge suggests that the research community should shift its focus from the soma to the axonal compartment of dopaminergic neurons.'I had been sitting on these data for two years before I submitted the paper' -said Dr. Jeffrey Kordower in the first talk of the Workshop, referring to his initial skepticism about the finding published in 2013 that in brains of PD patients, only 3-7 years after the diagnosis the putamen is almost completely depleted of TH-positive axons, while numerous cell bodies in the SNpc remain because the death of these neurons occurs at much slower pace [1]. It is not known if the axons had already degenerated at 3-7 years after diagnosis, or they are still there, just not expressing TH and other molecules involved in production and maintenance of functional dopaminergic synapses. Unfortunately, it has not been possible to address those questions in post-mortem human brains, as a structural marker specific for dopaminergic axons is not available, and striatum is innervated by axons from multiple nuclei including the cortex, amygdala, and raphe.Dr. Kordower also highlighted that studies with the growth factors GDNF/neurturin in monkeys and PD patients have suggested that nigrostriatal pathway axons need to be preserved for functional recovery to occur [2,3]. Moreover, the restoration of the nigrostriatal pathway alone is not necessarily translated to functional benefits as formation of synapses with the right target is also required.Degenerative changes that eventually lead to PD diagnosis start several years before the disease is discovered, and it is possible that loss of synaptic function in dopaminergic neurons is one of the first changes. Dr. Jon Stoessl presented the functional imaging data from PD patients showing evidence for early changes in striatal dopaminergic terminals [4]. The changes in effective dopamine turnover in the caudate and the putamen...

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