Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway

Abstract

20The sirtuins are highly conserved nicotinamide adenine dinucleotide (NAD + )-dependent en-21 zymes that play a broad role in cellular metabolism and aging. Mitochondrial sirtuin 3 22 (SIRT3) is downregulated in aging and age-associated diseases such as cancer and neuro-23 degeneration and plays a major role in maintaining mitochondrial function and preventing 24 oxidative stress. Mitochondria dysfunction is central to the pathogenesis of Parkinson disease 25 with mutations in mitochondrial-associated proteins such as PINK1 and parkin causing famil-26 ial Parkinson disease. Here, we demonstrate that the presence of alpha-synuclein (αsyn) oli-27 gomers in mitochondria induce a corresponding decrease in mitochondrial SIRT3 activity and 28 decreased mitochondrial biogenesis. We show that SIRT3 downregulation in the presence of 29 αsyn accumulation is accompanied by increased phosphorylation of AMP-activated protein 30 kinase (AMPK) and cAMP-response element binding protein (CREB), as well as increased 31 phosphorylation of dynamin-related protein 1 (DRP1) and decreased levels of optic atrophy 1 32 (OPA1), which is indicative of impaired mitochondrial dynamics. Treatment with the AMPK 33 agonist 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) restores SIRT3 ex-34 pression and activity and improves mitochondrial function by decreasing αsyn oligomer for-35 mation. The accumulation of αsyn oligomers in mitochondria corresponds with SIRT3 down-36 regulation not only in an experimental cellular model, but also in vivo in a rodent model of 37 Parkinson disease, and importantly, in human post mortem brains with neuropathologically 38 confirmed Lewy body disease (LBD). Taken together our findings suggest that pharmacolog-39 ically increasing SIRT3 levels will counteract αsyn-induced mitochondrial dysfunction by 40 normalizing mitochondrial bioenergetics. These data support a protective role for SIRT3 in 41 Parkinson disease-associated pathways and reveals significant mechanistic insight into the 42 interplay of SIRT3 and αsyn. 43 44 45 46 Abbreviations: SIRT3, Sirtuin 3; α-synuclein; αsyn; AMPK, adenosine monophosphate acti-47 vated protein kinase; CREB, cAMP-response element binding protein; DRP1, dynamin-48 related protein 1; OPA1, optic atrophy 1; HO-1, heme oxygenase-1; SOD2, superoxide dis-49 mutase 2; mtROS, mitochondrial reactive oxygen species. 50 51Alpha-synuclein (αsyn) accumulation is believed to be a key step in the pathogenesis of Par-53 kinson's disease and related alpha-synucleinopathies. Despite predominant localization in the 54 cytosol, αsyn is found localized to mitochondria in post-mortem Parkinson's disease brain 55 (Devi et al., 2008). Mitochondrial accumulation of αsyn has been associated with impairment 56 of complex-I dependent respiration, decreased mitochondria membrane potential, and in-57 creased levels of mitochondrial reactive oxygen species (mtROS) in multiple cellular models 58 (Hsu et al., 2000; Devi et al., 2008; Reeve et al., 2015; Ludtmann et al., 2018). The evidence 59 suppo...

SIRT3 Regulation of Mitochondrial Quality Control in Neurodegenerative Diseases

“…Studies have also shown that SIRT3 downregulation in the presence of α-synuclein accumulation is accompanied by increased phosphorylation of AMPK, cAMP-response element-binding protein (CREB), and DRP1, as well as decreased levels of OPA1. These results imply impaired mitochondrial dynamics, further supporting the protective role of SIRT3 in relevant PD pathways (Park et al, 2018).…”

Doxycycline inhibits α-synuclein-associated pathologiesin vitroandin vivo

“…Mitochondrial dysfunction leads to the production of reactive oxygen species and can directly interact with variety of specific proteins to be involved in neurodegenerative disorders (Lin & Beal, 2006). For example, in PD aSyn aggregates may induce neurodegeneration by causing a mitochondrial dysfunction and, thereby, the increased production of reactive oxygen species (ROS) (Park et al, 2020; Santos & Outeiro, 2020; Szegő É et al, 2019; Wang et al, 2019). For this reason, we measured intracellular ROS production in differentiated SH-SY5Y cells treated with aggregates formed in the absence or presence of 100 μM doxycycline.…”

“…It may also cause mitochondrial dysfunction and enhanced production of ROS, which may, in turn, further modulate aSyn oligomerization and cytotoxicity, leading to a vicious circle. The generation of ROS by aSyn aggregates can affect macromolecules or activate signalling pathways that culminate in central nervous system neurodegeneration (Park et al, 2020; Wang et al, 2019). For this reason, the inhibition of oxidative stress could offer an effective therapeutic approach to mitigate the progression of PD.…”

From Synaptic Protein to Prion: The Long and Controversial Journey of α-Synuclein

“…Based on in vitro and in vivo studies, α-syn seems to play a central role in the pathological changes through a direct interaction with components of cellular pathways essential for cell homeostasis (Figure 2). Thus, pathological α-syn is able to bind and inhibit lysosomal function (Mazzulli et al, 2016;Flavin et al, 2017), proteasomal activity (Stefanis et al, 2001;Tanaka et al, 2001;Petrucelli et al, 2002;Snyder et al, 2003;Lindersson et al, 2004;Emmanouilidou et al, 2010), to impair axonal transport (Volpicelli-Daley, 2017), and to induce Ca 2+ dyshomeostasis (Danzer et al, 2007;Chen Y. et al, 2015;Angelova et al, 2016) and mitochondrial dysfunction (Di Maio et al, 2016;Ganjam et al, 2019;Wang et al, 2019;Park et al, 2020). Latter promotes the generation of reactive oxygen species (ROS), and therefore oxidative stress, which may lead to mitochondrial damage, the release of cytochrome c to the cytoplasm, and cell death (Hsu et al, 2000;Smith et al, 2005;Parihar et al, 2008;Reeve et al, 2015;Tapias et al, 2017;Ludtmann et al, 2018).…”