LRRK2 G2019S Parkinson’s Disease Mutation and Astrocyte-Neuron Crosstalk: How Diseased Astrocytes Program the Susceptibility to Inflammation and Oxidative Stress Predisposing to Nigrostriatal Degeneration
LRRK2 G2019S Parkinson’s Disease Mutation and Astrocyte-Neuron Crosstalk: How Diseased Astrocytes Program the Susceptibility to Inflammation and Oxidative Stress Predisposing to Nigrostriatal Degeneration
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Original abstract
A complex interplay between genes and environmental factors is recognized to contribute to the death of dopaminergic neurons in the midbrain (mDAn) in Parkinson’s disease (PD). Within the known genes associated with PD, there is Leucine-Rich Repeat Kinase (LRRK2), recognized as one most frequent causes of PD, of either familial or sporadic nature. On the other hand, the mechanisms involved in LRRK2 dysfunction that contribute to PD pathogenesis are not defined. Within the environmental factors that are involved in PD pathogenesis, there is the ageing process and inflammatory reactions, as crucial actors participating to the vulnerability to both PD and also LRRK2-PD. Both processes, i.e., ageing and inflammation, can result in increased activation of glial cells, i.e. astrocytes and microglia. Remarkably, earlier and more recent evidence corroborate “a developmental hypothesis” for PD pathogenesis, whereby genes, crucial transcription factors and developmental pathways linked to mDAn vulnerability, interacting with early life events and key hormonal and inflammatory/anti-inflammatory signalling systems, are suspected to play important roles via their expression and/or intimate dialogue with astrocytes, as developed in this work, putting forward the hypothesis that early developmental astrocyte-neuron crosstalk dysregulation may predispose individuals to increased neuronal vulnerability later in life. Of importance, as herein reviewed, the interactions between astrocytes and neurons play a vital role during development as well as in the adult brain. In our laboratory we have been studying for at least thirty years the role, mechanisms and consequences of a physiological or pathological dialogue between mDAns and astrocytes during the development of mDAns, as well as during an inflammatory/oxidative stress response and brain ageing. Here, we aimed at reviewing the evidence in support of a decisive role of LRRK2-diseased astrocytes as predisposing elements for PD susceptibility, asking a. whether and how a malfunction of astrocyte-neuron crosstalk during development might in turn affect dopaminergic neuron vulnerability in adult life; b. what underlying mechanisms of LRRK2-astrocytes are involved ; c. the extent to which astrocyte-microglia maladaptive interactions form part of such dysfunctional interplay; d. what are the consequences for programming the susceptibility of mDAns in adult life and ageing, with their implications for the ongoing understanding of PD pathology and therapeutic developments targeting the dynamics of astrocyte-neuron dialogue.