Mitochondrial fitness influences neuronal excitability of dopaminergic neurons from patients with idiopathic form of Parkinson’s disease

Abstract

AbstractParkinson disease is the second most common neurodegenerative disease defined by presence of Lewy bodies and the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). There are three types of PD - familial, early-onset and idiopathic. Idiopathic PD (IPD) accounts for approximately 90% of all PD cases. Mitochondrial dysfunction accompanies the pathogenesis of Parkinson’s disease. Loss of mitochondrial function increases oxidative stress and calcium buffering, which in turn hinders the production of ATP and disrupts the functioning of dopaminergic neurons. The main barrier in PD research was the lack of proper human models to study the mechanisms of PD development and progression. Using induced pluripotent stem (iPS) cells we generated patient-specific dopaminergic neurons.We observed differences in the mitochondria fitness but not differences in mitochondria mass, morphology or membrane potential. Expression of OXPHOS mitochondrial complexes were lower in PD patients in comparison to control group what resulted in changes in mitochondria respiratory status. We observed also lower expression levels of Na+/K+-ATPase subunits and ATP-sensitive K+(K-ATP) channel subunits. The lower oxygen consumption rate and extracellular acidification rate values were observed in dopaminergic progenitors and iPSC from PD patients compared to the control group. Importantly, observed decrease in the availability of ATP and in the energy consumption, as well as changes in acidification, may constitute contributing factors to the observed reduced neuronal excitability of PD patients dopaminergic neurons.