Alpha-synuclein in the progression of Parkinson's disease: to seed or not to seed, that is the question

Francisco Pan-Montojo MD, PhD
Head of SyNergy Clinician Scientist Group
Munich Cluster for Systems Neurology
Klinikum der Universität München

Alpha-synuclein in the progression of Parkinson's disease: to seed or not to seed, that is the question

Parkinson´s disease (PD) pathology progresses throughout the nervous system affecting numerous neuronal structures. LB and LN are intracellular protein inclusions pathognomonic for PD pathology. Alpha-synuclein (ASYN) is the main component of Lewy Bodies and Neurites (LB and LN). It has been postulated that the progression of the pathology is based on a prion-like disease mechanism partly due to the seeding effect of endocytosed ASYN on the endogenous ASYN. The appearance of the pathology in dopaminergic neurons leads to neuronal cell death and motor symptoms. However, the effect on other neuronal structures is more inconsistent, leading to a higher variability in the prevalence of non-motor symptoms. Thus, suggesting that the sensitivity to the pathology varies among neuronal subtypes. Here, we analyzed the effect of monomeric and oligomeric ASYN on primary enteric, sympathetic, dopaminergic and cortical neurons from wild-type mice. Our results show that dopaminergic neurons are more sensitive to ASYN when compared to all other neuronal subtypes. This difference in the toxic effect of ASYN was independent of the presence of endogenous ASYN and directly related to the impairment of the mitochondrial function. Altogether, our results suggest that the interaction between ASYN and mitochondria and not a seeding effect on the endogenously produced protein is alone responsible for the toxic effect of extracellular ASYN.  These results question the prion-disease hypothesis and suggest a different new mechanism by which PD-pathology progresses through the impairment of the host´s mitochondria.

Biography:

I Studied medicine in Madrid, Spain. I did my medical doctor thesis and my PhD in Dresden at the International Max-Planck School. I was trained as a postdoc with Teymuras Kurzchalia at MPI Dresden. During all this time I also trained in my specialty - Neurology at the Carl Gustav Carus hospital in parallel. Since 2014, I have a research group at the Excellence Cluster “Munich Cluster für Systems Neurology” and work in the clinic as a neurologist.