Emerging Roles for Aberrant Astrocytic Calcium Signals in Parkinson's Disease

Abstract

Astrocytes display a plethora of spontaneous Ca²⁺ signals that modulate vital functions of the central nervous system (CNS). This suggests that astrocytic Ca²⁺ signals also contribute to pathological processes in the CNS. In this context, the molecular mechanisms by which aberrant astrocytic Ca²⁺ signals trigger dopaminergic neuron loss during Parkinson's disease (PD) are only beginning to emerge. Here, we provide an evidence-based perspective on potential mechanisms by which aberrant astrocytic Ca²⁺ signals can trigger dysfunction in three distinct compartments of the brain, viz., neurons, microglia, and the blood brain barrier, thereby leading to PD. We envision that the coming decades will unravel novel mechanisms by which aberrant astrocytic Ca²⁺ signals contribute to PD and other neurodegenerative processes in the CNS.

Keywords: Parkinson’s disease; astrocytes; calcium; mitochondria; neurodegenenerative diseases.

FIGURE 1

Aberrant astrocytic Ca²⁺ signals contribute to Parkinson’s disease pathology via multiple mechanisms. Neuronal interactions. Dopamine surges during early PD may dysregulate astrocytic Ca²⁺ signals and lead to EAAT2 internalization, leading to reduced glutamate clearance and initiation of excitotoxic cell death for dopaminergic midbrain neurons. Disruptions in astrocytic mitochondria Ca²⁺ signals (triggered from protein aggregates such as α-synuclein) lead to reduced ATP production, alteration of mitochondria-ER tethering, likely contributing to dopaminergic neurodegeneration. Microglial interactions. Aberrant astrocytic Ca²⁺ signals drive mislocalization of AQP4 channels in astrocytes. AQP4 deficiency in astrocytes is associated with increases in microglial activity and further secretion of inflammatory cytokines, ultimately contributing to dopaminergic neurodegeneration. Aberrant astrocytic Ca²⁺ signals may drive increased secretion of ApoE4 which leads to microglial reactivity, increased α-synuclein pathology and eventually dopaminergic neurodegeneration. Blood brain barrier (BBB) interactions. Aberrant Ca²⁺ signals in astrocyte endfeet may result in altered secretion of neurotrophic factors such as GDNF, leading to dysregulation of tight junction proteins (TJPs), compromised BBB integrity, and further contribute to dopaminergic neurodegeneration.