Abstract
Twelve-month-old male mice expressing the human A53T variant of α-synuclein (A53T) develop dopamine neuron degeneration, neuroinflammation, and motor deficits, along with dysfunctions of the mitochondrial Na+-Ca2+ exchanger (NCX) isoforms 1 (NCX1) and 3 (NCX3) in the nigrostriatal system. Since gender is thought to play a role in the etiology of Parkinson’s disease (PD), we characterized neurochemical and behavioral alterations in 12-month-old female A53T transgenic mice. We investigated the presence of dopaminergic degeneration, astrogliosis and microgliosis using immunohistochemistry for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 (IBA-1) in both the substantia nigra pars compacta (SNc) and striatum. In the same regions, we also evaluated the co-localization of NCX1 in cells positive for IBA-1 and the co-localization of NCX3 in TH-positive neurons and fibers. Furthermore, in both male and female mice, we performed motor (beam walking and pole tests) and memory [novel object recognition (NOR) and spontaneous alternation] tasks, together with tests to evaluate peripheral deficits (olfactory and stool collection tests). Female A53T transgenic mice displayed degeneration of nigral dopaminergic neurons, but neither microgliosis nor astrogliosis in the SNc and striatum. Moreover, female A53T transgenic mice displayed co-localization between NCX1 and IBA-1 positive cells in the striatum but not SNc, whereas NCX3 did not co-localize with either TH-positive terminals or neuronal bodies in the nigrostriatal system. Furthermore, female A53T transgenic mice showed increased crossing time in the beam walking test, but no impairments in the pole or memory tests, and in tests that evaluated peripheral deficits, whereas male A53T transgenic mice displayed motor, memory and peripheral deficits. Immunohistochemical and behavioral results obtained here in the female mice differ from those previously observed in males, and suggest a dissimilar influence of NCX1 and NCX3 on dopaminergic function in female and male A53T transgenic mice, strengthening the validity of these mice as a model for studying the etiological factors of PD.
Highlights
Parkinson’s disease (PD) is a complex neurodegenerative disorder characterized by the demise of dopaminergic neurons in the substantia nigra pars compacta (SNc) and by the reduction of dopaminergic tone at the level of the striatum (Obeso et al, 2010, 2017; Halliday et al, 2011; Costa and Morelli, 2015)
tyrosine hydroxylase (TH)-positive nigral neurons and striatal fibers were decreased in male A53T transgenic mice, and these effects were accompanied by an increase of glial fibrillary acidic protein (GFAP)-positive astroglial cells in the SNc and striatum, as well as of ionized calcium-binding adaptor molecule 1 (IBA-1)-positive cells in the striatum
These data led us to conclude that abnormalities in the NCX1 and NCX3, which regulate cytosolic and mitochondrial Ca2+ homeostasis in the midbrain and striatum, might play a role in the dopaminergic nigrostriatal degeneration and in the neuroinflammation that occurs in 12-month-old male A53T transgenic mice (Sirabella et al, 2018)
Summary
Parkinson’s disease (PD) is a complex neurodegenerative disorder characterized by the demise of dopaminergic neurons in the substantia nigra pars compacta (SNc) and by the reduction of dopaminergic tone at the level of the striatum (Obeso et al, 2010, 2017; Halliday et al, 2011; Costa and Morelli, 2015). An upregulation of genes involved in signal transduction and neuronal maturation was observed in parkinsonian women, while an upregulation of genes implicated in the pathogenesis of PD (α-synuclein and PINK1) was found in parkinsonian men (Cantuti-Castelvetri et al, 2007). Another possible explanation for the gender effect observed in PD may involve alterations in mitochondrial function (Briston and Hicks, 2018; Reeve et al, 2018; McAvoy and Kawamata, 2019), and in particular an impairment in complex I of the electron transport system. One study that genotyped the polypeptides encoded by the mitochondrial genome in both PD patients and general population found that the single-nucleotide polymorphism
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