Abstract
The appearance of alpha-synuclein-positive inclusion bodies (Lewy bodies) and the loss of catecholaminergic neurons are the primary pathological hallmarks of Parkinson’s disease (PD). However, the dysfunction of mitochondria has long been recognized as a key component in the progression of the disease. Dysfunctional mitochondria can in turn lead to dysregulation of calcium homeostasis and, especially in dopaminergic neurons, raised mean intracellular calcium concentration. As calcium binding to alpha-synuclein is one of the important triggers of alpha-synuclein aggregation, mitochondrial dysfunction will promote inclusion body formation and disease progression. Increased reactive oxygen species (ROS) resulting from inefficiencies in the electron transport chain also contribute to the formation of alpha-synuclein aggregates and neuronal loss. Recent studies have also highlighted defects in mitochondrial clearance that lead to the accumulation of depolarized mitochondria. Transaxonal and intracytoplasmic translocation of mitochondria along the microtubule cytoskeleton may also be affected in diseased neurons. Furthermore, nanotube-mediated intercellular transfer of mitochondria has recently been reported between different cell types and may have relevance to the spread of PD pathology between adjacent brain regions. In the current review, the contributions of both intracellular and intercellular mitochondrial dynamics to the etiology of PD will be discussed.
Highlights
The principal histopathological marker of Parkinson’s disease (PD) is the presence in neurons of α-synuclein (α-syn) protein aggregates that occur in inclusion bodies known as Lewy bodies (Shults, 2006; McCann et al, 2014). α-Syn is primarily expressed pre-synaptically and evidence exists of α-syn transfer from neurons to neuronal and non-neuronal cells in vitro, indicating that α-syn pathology spreads between anatomically adjacent brain regions by a cell-to-cell transfer mechanism (Valdinocci et al, 2017). α-Syn is a small (14 kDa), acidic protein expressed in the brain, peripheral nervous system and circulating erythrocytes (Thakur et al, 2019)
Α-Syn can be located at mitochondrial membranes, especially under stress conditions (Cole et al, 2008; Devi et al, 2008), and its aggregation can be linked to mitochondrial dysfunction in PD (Perfeito et al, 2013; Celardo et al, 2014). α-Syn aggregates may in turn cause deleterious alterations in mitochondrial function, including intracellular dynamics
Mitochondria constantly undergo cycles of fusion and fission that affect their morphology and shape, processes that may be perturbed in PD. α-Syn has been shown to influence mitochondrial size both independently and dependent on fusion/fission proteins, with recent reports detailing these interactions as an attribute of the pathological variants such as oligomers and fibrils, ruling out any negative effects on mitochondrial dynamics as a normal function of the monomer (Wang et al, 2019)
Summary
The principal histopathological marker of Parkinson’s disease (PD) is the presence in neurons of α-synuclein (α-syn) protein aggregates that occur in inclusion bodies known as Lewy bodies (Shults, 2006; McCann et al, 2014). α-Syn is primarily expressed pre-synaptically and evidence exists of α-syn transfer from neurons to neuronal and non-neuronal cells in vitro, indicating that α-syn pathology spreads between anatomically adjacent brain regions by a cell-to-cell transfer mechanism (Valdinocci et al, 2017). α-Syn is a small (14 kDa), acidic protein expressed in the brain, peripheral nervous system and circulating erythrocytes (Thakur et al, 2019). In vitro α-syn is a dynamically unfolded protein, in vivo the membrane-associated tetrameric form is proposed to be α-helical (Bartels et al, 2011). Various factors, such as raised copper or calcium concentration, oxidative stress and post-translational modifications can trigger intracellular α-syn aggregation (Fujiwara et al, 2002; El-Agnaf et al, 2006; Reynolds et al, 2008; Rcom-H’cheo-Gauthier et al, 2016). Α-Syn can be located at mitochondrial membranes, especially under stress conditions (Cole et al, 2008; Devi et al, 2008), and its aggregation can be linked to mitochondrial dysfunction in PD (Perfeito et al, 2013; Celardo et al, 2014). Α-Syn aggregates may in turn cause deleterious alterations in mitochondrial function, including intracellular dynamics. This review focusses on α-syn interactions with mitochondria in PD
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