Formal model of Parkinson's disease neurons unveils possible causality links in the pathophysiology of the disease

Abstract

Parkinsons Disease is the second most common neurodegenerative disease after Alzheimers disease. Despite extensive research, the initial cause of the disease is still unknown, although substantial advances were made in understanding of its genetics and the cognate neurophysiological mechanisms. Determining the causality relationships and the chronological steps pertaining to Parkinsons Disease is essential for the discovery of novel drug targets. We developed a systematic in silico model based on available data, which puts the possible sequence of events occurring in a neuron during disease onset into light. This is the first ever attempt, to our knowledge, to model comprehensively the primary modifications in the molecular pathways that manifest in compromised neurons from the commencement of the disease to the consequences of its progression. We showed that our proposed disease pathway was relevant for unveiling yet incomplete knowledge on calcium homeostasis in mitochondria, ROS production and -synuclein misfolding. Graphical abstract HighlightsO_LIVarying calcium concentration in aging dopaminergic neurons triggers disease onset. C_LIO_LIROS production in the mitochondria potentially causes iron accumulation. C_LIO_LIIron homeostasis dysregulation is linked to -synuclein aggregation. C_LI