Abstract
The loss of dopaminergic (DA) neurons in the substantia nigra leads to a progressive, long-term decline of movement and other non-motor deficits. The symptoms of Parkinson’s disease (PD) often appear later in the course of the disease, when most of the functional dopaminergic neurons have been lost. The late onset of the disease, the severity of the illness, and its impact on the global health system demand earlier diagnosis and better targeted therapy. PD etiology and pathogenesis are largely unknown. There are mutations in genes that have been linked to PD and, from these complex phenotypes, mitochondrial dysfunction emerged as central in the pathogenesis and evolution of PD. In fact, several PD-associated genes negatively impact on mitochondria physiology, supporting the notion that dysregulation of mitochondrial signaling and homeostasis is pathogenically relevant. Derangement of mitochondrial homeostatic controls can lead to oxidative stress and neuronal cell death. Restoring deranged signaling cascades to and from mitochondria in PD neurons may then represent a viable opportunity to reset energy metabolism and delay the death of dopaminergic neurons. Here, we will highlight the relevance of dysfunctional mitochondrial homeostasis and signaling in PD, the molecular mechanisms involved, and potential therapeutic approaches to restore mitochondrial activities in damaged neurons.
Highlights
Mitochondria are the powerhouses of the cell and play an essential role in different metabolic pathways
Loss of leucine-rich repeat kinase 2 (LRRK2) activity or a Parkinson’s disease (PD)-linked missense mutation within the RIIβ-binding domain (R1441C) of LRRK2 aberrantly induced a widespread, uncontrolled protein kinase A (PKA) phosphorylation of cellular substrates, including glutamate ionotropic receptor AMPA type subunit 1 (GluR1; Muda et al, 2014; Parisiadou et al, 2014). These findings indicate the existence of a mutual control of LRRK2 and PKA activities within dopaminergic neurons, and derangement of this control circuitry may have a pathogenetic relevance for PD
Important progress has been made to improve early diagnosis and to identify the relevant pathogenetic factors and mechanisms involved in the selective loss of dopaminergic neurons
Summary
Mitochondria are the powerhouses of the cell and play an essential role in different metabolic pathways. Signaling pathways play a major role in mitochondrial activities, including oxidative phosphorylation, cell survival, metabolism, intracellular calcium homeostasis, organelle biogenesis/turnover, and dynamics. Upregulation of cAMP signaling to the organelle by AKAPs or pharmacological interference with mitochondriagenerated apoptotic pathways reversed oxidative stress, mitochondrial dysfunction, and loss of dopaminergic neurons in PD models (Dagda et al, 2011; Kostic et al, 2015).
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