Abstract
Na+-Ca2+ exchanger (NCX) isoforms constitute the major cellular Ca2+ extruding system in neurons and microglia. We herein investigated the role of NCX isoforms in the pathophysiology of Parkinson’s disease (PD). Their expression and activity were evaluated in neurons and glia of mice expressing the human A53T variant of α-synuclein (A53T mice), an animal model mimicking a familial form of PD. Western blotting revealed that NCX3 expression in the midbrain of 12-month old A53T mice was lower than that of wild type (WT). Conversely, NCX1 expression increased in the striatum. Immunohistochemical studies showed that glial fibrillary acidic protein (GFAP)-positive astroglial cells significantly increased in the substantia nigra pars compacta (SNc) and in the striatum. However, the number and the density of tyrosine hydroxylase (TH)-positive neurons decreased in both brain regions. Interestingly, ionized calcium binding adaptor molecule 1 (IBA-1)-positive microglial cells increased only in the striatum of A53T mice compared to WT. Double immunostaining studies showed that in A53T mice, NCX1 was exclusively co-expressed in IBA-1-positive microglial cells in the striatum, whereas NCX3 was solely co-expressed in TH-positive neurons in SNc. Beam walking and pole tests revealed a reduction in motor performance for A53T mice compared to WT. In vitro experiments in midbrain neurons from A53T and WT mice demonstrated a reduction in NCX3 expression, which was accompanied by mitochondrial overload of Ca2+ ions, monitored with confocal microscopy by X-Rhod-1 fluorescent dye. Collectively, in vivo and in vitro findings suggest that the reduction in NCX3 expression and activity in A53T neurons from midbrain may cause mitochondrial dysfunction and neuronal death in this brain area, whereas NCX1 overexpression in microglial cells may promote their proliferation in the striatum.
Highlights
Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantiaIn addition to dopaminergic degeneration in the substantia nigra pars compacta (SNc), PD is neuropathologically characterized by the presence of Lewy bodies and intracytoplasmic eosinophilic inclusions in injured or fragmented neurons[4], with α-synuclein as the major fibrillary component[5]
NCX1 increases in striatum, whereas NCX3 decreases in midbrain of 12-month-old A53T mice To understand the role of the Na+-Ca2+ exchanger (NCX) isoforms in the pathophysiology of PD, we performed Western blot experiments in A53T and wild type (WT) mice, the former being a mouse model of a familial form of the disease
We found that NCX1 levels were increased in the striatum of A53T mice (Fig. 1a), whereas NCX2 and NCX3 levels were similar to those of WT (Fig. 1b, c)
Summary
Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantiaIn addition to dopaminergic degeneration in the SNc, PD is neuropathologically characterized by the presence of Lewy bodies and intracytoplasmic eosinophilic inclusions in injured or fragmented neurons[4], with α-synuclein as the major fibrillary component[5]. Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia. The exact mechanism underlying selective mesostriatal dopaminergic. Many cellular mechanisms are known to be involved in the pathogenesis of PD, including oxidative stress[6], intracellular Ca2+ homeostasis impairment[7], and mitochondrial dysfunction[8]. Epidemiological, and experimental evidence has pinpointed neuroinflammation as a major driver of disease progression and glial cell activation as a key player in dopaminergic neuronal degeneration[9]. Studies of the SNc from patients with PD and of. A study performed in monkeys overexpressing the A53T variant of α-synuclein[13] shows that dopaminergic neuronal degeneration is associated with long-term microgliosis in the midbrain—a finding of particular relevance since it correlates misfolded α-synuclein with glial activation
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