Calcium CaV1 Channel Subtype mRNA Expression in Parkinson’s Disease Examined by In Situ Hybridization

Abstract

The factors which make some neurons vulnerable to neurodegeneration in Parkinson's disease while others remain resistant are not fully understood. Studies in animal models of Parkinson's disease suggest that preferential use of CaV1.3 subtypes by neurons may contribute to the neurodegenerative process by increasing mitochondrial oxidant stress. This study quantified the level of mRNA for the CaV1 subtypes found in the brain by in situ hybridization using CaV1 subtype-specific [(35)S]-radiolabelled oligonucleotide probes. In normal brain, the greatest amount of messenger RNA (mRNA) for each CaV1 subtype was found in the midbrain (substantia nigra), with a moderate level in the pons (locus coeruleus) and lower quantities in cerebral cortex (cingulate and primary motor). In Parkinson's disease, the level of CaV1 subtype mRNA was maintained in the midbrain and pons, despite cell loss in these areas. In cingulate cortex, CaV1.2 and CaV1.3 mRNA increased in cases with late-stage Parkinson's disease. In primary motor cortex, the level of CaV1.2 mRNA increased in late-stage Parkinson's disease. The level of CaV1.3 mRNA increased in primary motor cortex of cases with early-stage Parkinson's disease and normalized to near the control level in cases from late-stage Parkinson's disease. The finding of elevated CaV1 subtype expression in cortical brain regions supports the view that disturbed calcium homeostasis is a feature of Parkinson's disease throughout brain and not only a compensatory consequence to the neurodegenerative process in areas of cell loss.

Alpha‐synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation

“…An action on the early phase can also be envisioned if expression of CaV1.3 channels partly is regulated by negative feedback from average cytosolic calcium levels. The increased levels of CaV1.3 antigen and mRNA in cortical tissue with no Lewy body pathology from early PD patients [4,5] could represent a response to soluble AS oligomers activating SERCA and reducing average Ca 2+ in neurons not exhibiting spontaneous pace making changes in Ca 2+ as in dopaminergic neurons of substantia nigra pars compacta. The ongoing clinical study of early PD patients treated with L-type Ca channel antagonist isradipine may inform about these issues in the near future (ClinicalTrials.gov Identifier: NCT02168842).…”

A Cortical Pathogenic Theory of Parkinson’s Disease

“…On the other hand, prodromal alterations in motor cortex plasticity are supported by pathological investigations on Ca 2+ channels, which are critical in the regulation of cortical excitability and plasticity (Wankerl et al, 2010;Verhoog et al, 2013;Weise et al, 2017). Specifically, recent postmortem studies show increased expression of L-type voltagegated Ca 2+ channels in the primary motor cortex at least as early as Braak's stages III-IV (Hurley et al, 2013(Hurley et al, , 2015b, and molecular alterations in motor cortical areas have also been reported in incidental Lewy body disease at Braak's stages I-II (Hurley et al, 2015a;Santpere et al, 2018). Motor cortical areas thus seem to be altered well before the appearance of cortical Lewy pathology (Braak's stages V-VI) and before the onset of motor features in PD.…”

Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease

“…Sustained Ca 2+ entry through Cav1 channels in forebrain neurons has long been associated with aging-related cognitive decline and AD (Disterhoft et al, 1994; Thibault et al, 2007). Moreover, in cPD patients, Cav1 Ca 2+ channels are up-regulated in limbic and motor cortices (Hurley et al, 2013; 2014). …”