Synucleinopathy disorders: A tale of two neurotransmitters

Synucleinopathies consist of several neurodegenerative disorders which have in common the progressive loss of brain cells, accompanied by the formation of microscopic protein aggregates within remaining neurons. Although symptoms and neuropathological features overlap to some extent, patho-clinical features are also distinct between the syndromes, indicating different underlying disease mechanisms. We previously conducted single-cell analyses of neurons taken from Parkinson’s disease (PD) post-mortem brains. The results revealed profound mitochondrial DNA (mtDNA) differences between remaining (but susceptible to undergoing neurodegeneration) neurons of different neurochemical types, namely mesencephalic dopaminergic compared to PPN cholinergic neurons. This indicates that mtDNA are affected differently, depending on neuronal type, in synucleinopathy patients. My talk will cover recent and ongoing studies in my lab that analyse single-cell, type specific neurons from post-mortem synucleinopathy brains, to better understand mDNA variance patterns between vulnerable neurons, particularly catecholaminergic (i.e. dopaminergic and noradrenergic) and cholinergic neurons. In addition, I will report on a new cholinergic-synucleinopathy model system we are developing, which shows mitochondrial dysfunction. Understanding the underlying mechanisms to explain differential neurotype-specific vulnerabilities for synucleinpathy disorders may allow for improved therapies that are tailored to correct mtDNA deficiencies in a cell-type specific manner, hence avoiding side-effects from non-intended cellular targets.