Abstract
The presynaptic protein alpha-synuclein (α-syn) is unequivocally linked to the development of Parkinson’s disease (PD). Not only it is the major component of amyloid fibrils found in Lewy bodies but mutations and duplication/triplication in its gene are responsible for the onset of familial autosomal dominant forms of PD. Nevertheless, the precise mechanisms leading to neuronal degeneration are not fully understood. Several lines of evidence suggest that impaired autophagy clearance and mitochondrial dysfunctions such as bioenergetics and calcium handling defects and alteration in mitochondrial morphology might play a pivotal role in the etiology and progression of PD, and indicate the intriguing possibility that α-syn could be involved in the control of mitochondrial function both in physiological and pathological conditions. In favor of this, it has been shown that a fraction of cellular α-syn can selectively localize to mitochondrial sub-compartments upon specific stimuli, highlighting possible novel routes for α-syn action. A plethora of mitochondrial processes, including cytochrome c release, calcium homeostasis, control of mitochondrial membrane potential and ATP production, is directly influenced by α-syn. Eventually, α-syn localization within mitochondria may also account for its aggregation state, making the α-syn/mitochondria intimate relationship a potential key for the understanding of PD pathogenesis. Here, we will deeply survey the recent literature in the field by focusing our attention on the processes directly controlled by α-syn within mitochondrial sub-compartments and its potential partners providing possible hints for future therapeutic targets.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting more than 50000 people each year only in the US1,2
Alterations of mitochondrial membrane potential, increased reactive oxygen species (ROS) production and mitochondrial vacuolation, swallowing and loss of cristae observed upon α-syn overexpression are partially reverted by the incubation with the adenine nucleotide translocase (ANT) inhibitor bongkrekic acid (BKA), which was shown to reduce the interaction between α-syn and both ANT and VDAC, suggesting that this interaction could be the key for α-syn detrimental activity (Shen et al, 2014)
Mitochondrial dysfunctions and α-syn misfolding/aggregation have both been extensively documented in the pathogenesis of PD (Exner et al, 2012; Bose and Beal, 2016)
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting more than 50000 people each year only in the US1,2. We have shown that addition of exogenous recombinant α-syn to cell cultures leads to a dose dependent impairment of Ca2+ handling, with different doses showing different effects: increased mitochondrial Ca2+ transients were observed upon incubation with the 4 μM exogenous α-syn, whereas a reduction was measured upon treatment with 8 μM (Calì et al, 2012) Another group reported that α-syn-induced mitochondrial fragmentation is dependent on its expression levels: whereas the expression of low levels of wt, A53T or A30P α-syn induced mitochondrial fragmentation only in the case of A53T, higher expression of the protein resulted in mitochondrial fragmentation in the case of wt α-syn (Pozo Devoto et al, 2017). Α-syn was found at the MAMs (Guardia-Laguarta et al, 2014; Paillusson et al, 2017) and shown to interact with the ER vesicle-associated membrane protein-associated protein B (VAPB), perturbing its association with the protein tyrosine
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