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• W2885280818 abstract "Review31 July 2018free access Parkinson's disease: convergence on synaptic homeostasis Sandra-Fausia Soukup Corresponding Author [email protected] orcid.org/0000-0003-2915-919X VIB-KU Leuven Center for Brain& Disease Research, Leuven, Belgium Department of Neurosciences, KU Leuven, Leuven, Belgium Search for more papers by this author Roeland Vanhauwaert VIB-KU Leuven Center for Brain& Disease Research, Leuven, Belgium Department of Neurosciences, KU Leuven, Leuven, Belgium Search for more papers by this author Patrik Verstreken Corresponding Author [email protected] orcid.org/0000-0002-5073-5393 VIB-KU Leuven Center for Brain& Disease Research, Leuven, Belgium Department of Neurosciences, KU Leuven, Leuven, Belgium Search for more papers by this author Sandra-Fausia Soukup Corresponding Author [email protected] orcid.org/0000-0003-2915-919X VIB-KU Leuven Center for Brain& Disease Research, Leuven, Belgium Department of Neurosciences, KU Leuven, Leuven, Belgium Search for more papers by this author Roeland Vanhauwaert VIB-KU Leuven Center for Brain& Disease Research, Leuven, Belgium Department of Neurosciences, KU Leuven, Leuven, Belgium Search for more papers by this author Patrik Verstreken Corresponding Author [email protected] orcid.org/0000-0002-5073-5393 VIB-KU Leuven Center for Brain& Disease Research, Leuven, Belgium Department of Neurosciences, KU Leuven, Leuven, Belgium Search for more papers by this author Author Information Sandra-Fausia Soukup *,1,2, Roeland Vanhauwaert1,2,† and Patrik Verstreken *,1,2 1VIB-KU Leuven Center for Brain& Disease Research, Leuven, Belgium 2Department of Neurosciences, KU Leuven, Leuven, Belgium †Present address: Department of Neurosurgery, Stanford University, Palo Alto, CA, USA *Corresponding author. Tel: +32 16377035; E-mail: [email protected] *Corresponding author. Tel: +32 16330018; E-mail: [email protected] EMBO J (2018)37:e98960https://doi.org/10.15252/embj.201898960 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Parkinson's disease, the second most common neurodegenerative disorder, affects millions of people globally. There is no cure, and its prevalence will double by 2030. In recent years, numerous causative genes and risk factors for Parkinson's disease have been identified and more than half appear to function at the synapse. Subtle synaptic defects are thought to precede blunt neuronal death, but the mechanisms that are dysfunctional at synapses are only now being unraveled. Here, we review recent work and propose a model where different Parkinson proteins interact in a cell compartment-specific manner at the synapse where these proteins regulate endocytosis and autophagy. While this field is only recently emerging, the work suggests that the loss of synaptic homeostasis may contribute to neurodegeneration and is a key player in Parkinson's disease. Introduction Cells, also neurons, accumulate cellular debris, dysfunctional organelles, and proteins. However, the post-mitotic nature of neurons makes it impossible for them to dilute cellular debris through cell division. Moreover, neurons have an extensive cytoplasm: The volume of the cell body is often < 1% of the volume of the entire neuron. These features together with the need for intense metabolic activity during stimulation to sustain neurotransmission make neurons especially dependent on efficient mechanisms that control protein homeostasis. Synapses are often at a far distance from the cell body where proteins are synthesized and protein degradation has been shown to take place (reviewed in Hara et al, 2006; Kaushik & Cuervo, 2015). However, recent work indicates the existence of synapse-specific mechanisms that regulate protein turnover. These may be of particular importance in the context of neurodegenerative diseases (reviewed in Vijayan & Verstreken, 2017; Jin et al, 2018) that are often characterized by misfolded, aggregated, and dysfunctional proteins [e.g., α-Synuclein and LRRK2-containing Lewy bodies in Parkinson's disease (PD; Spillantini et al, 1997; Zhu et al, 2006)]. Neurodegeneration is often thought to start at synaptic contact sites, as these are the first cellular compartments that appear to be affected (Cheng et al, 2010; Burke & O'Malley, 2013). We therefore hypothesize that deciphering the mechanisms that function in synaptic protein homeostasis at synapses is critical to understand these diseases. We will argue that connections between synaptic protein homeostasis and the mechanisms of PD are particularly strong. The origin of PD is in many cases unknown: toxins, pesticides, and dysregulation of complex genetic interactions are thought to account for about 90–95% of cases. Familial monogenic mutations account for about 5–10% of the PD cases, and there are about 20 different genes that cause PD when mutated (“PD genes”). Some of the mutations are inherited in a dominant fashion while others are inherited recessively (see Table 1). Loss- and gain-of-function studies for most of these 20 genes have been conducted, and phenotypic analyses indicate that more than half of these “PD-genes” regulate synaptic function and protein turnover (see Table 1). These synaptic and protein turnover defects also appear pathologically relevant, because they are seen when pathogenic mutants of these “PD genes” were knocked in or over expressed in flies or mice (Table 1 and references therein). However, additional studies where pathogenic mutations are knocked into the endogenous locus or studies with human neurons derived from patients are needed to better model and understand these defects across the genetic space of PD. Nonetheless, the available data indicate that many of the genes mutated in PD encode proteins that regulate mechanisms of synaptic function. Table 1. Proposed function of familial Parkinson's disease genes Symbol Gene/Protein Mutation(s) Inheritance Biological process Synaptic function PARK1/4 SNCA/α-Synuclein A30P, E46K, H50Q, G51N, A53T, and multiplications AD Clathrin-mediated endocytosis Neurotransmitter release Exosome release Chaperone-mediated autophagy Yesaa Ribeiro et al (2002), Chandra et al (2005), Burré et al (2010), Westphal and Chandra (2013), Zaltieri et al (2015). PARK8 DARDARIN/LRRK2 N1437H, R1441H/G/C, Y1699C, G2019S, I2020T AD Clathrin-mediated endocytosis Autophagy Neurotransmitter release Endo-lysosomal trafficking Exosome release Yesbb Piccoli et al (2011), Matta et al (2012), Piccoli et al (2014), Arranz et al (2015), Islam et al (2016), Soukup et al (2016), Pan et al (2017). PARK17 VPS35/Vps35 D620N AD Autophagy Endo-lysosomal trafficking Golgi complex trafficking Yescc Munsie et al (2014), Inoshita et al (2017). PARK2 parkin/Parkin Numerous duplication and missense mutations AR Clathrin-mediated endocytosis Mitochondrial quality control neurotransmitter release Ubiquitination Tumorigenesis Yesdd Chung et al (2001), Huynh et al (2003), Beccano-Kelly et al (2014). PARK6 PINK1 Numerous deletions and point mutations AR Mitochondrial function Mitochondrial quality control Yesee Verstreken et al (2005). PARK7 PARK7/DJ-1 dup 168–185, A39S, E64D, D149A, Q163L, L166P, M261I AR Mitochondrial function mitochondrial quality control of reactive oxygen species transcription regulation Yesff Usami et al (2011). PARK9 ATP13A2/ATP13A2 M810R, G877R, missense, small insertions, and deletions AR Endo-lysosomal pathway Exosome release ND PARK14 PLA2G6 P806R, R301C, D331N AR Membrane trafficking Phospholipid metabolism Mitochondrial function ND PARK15 FBX07 T22M, L34R, R378G, and frameshift mutation AR Ubiquitination Proliferation ND PARK19 DNAJC6/Auxilin Q734X AR Clathrin-mediated endocytosis Golgi–lysosome trafficking Yesgg Edvardson et al (2012), Yim et al (2010). PARK20 SYNJ1/Synaptojanin 1 R258Q, R459P AR Clathrin-mediated endocytosis Synaptic autophagy Yeshh Cremona et al (1999), Gad et al (2000), Verstreken et al (2003), Schuske et al (2003), Mani et al (2007). PARK21 DNAJC13/RME-8 N855S AD Clathrin-mediated endocytosis Endosomal sorting/trafficking ND AD, autosomal dominant; AR, autosomal recessive. a Ribeiro et al (2002), Chandra et al (2005), Burré et al (2010), Westphal and Chandra (2013), Zaltieri et al (2015). b Piccoli et al (2011), Matta et al (2012), Piccoli et al (2014), Arranz et al (2015), Islam et al (2016), Soukup et al (2016), Pan et al (2017). c Munsie et al (2014), Inoshita et al (2017). d Chung et al (2001), Huynh et al (2003), Beccano-Kelly et al (2014). e Verstreken et al (2005). f Usami et al (2011). g Edvardson et al (2012), Yim et al (2010). h Cremona et al (1999), Gad et al (2000), Verstreken et al (2003), Schuske et al (2003), Mani et al (2007). Several of the genes implicated in PD encode proteins that are enriched at the presynaptic compartment, including DNAJC6/Auxilin, Synaptojanin 1 (Synj1), leucine-rich repeat kinase 2 (LRRK2), Endophilin A1 (EndoA), and α-Synuclein (Table 1). α-Synuclein is also often found aggregated in PD (in Lewy bodies), and dominant mutations or triplications cause the disease (Hope et al, 2004; Zarranz et al, 2004). Some studies suggest that the aggregation of proteins such as α-Synuclein may itself also alter pathways that guard synaptic homeostasis, e.g. by “clogging” protein turnover systems, thus causing a further buildup of dysfunctional proteins and organelles (Polymeropoulos et al, 1997; Kramer & Schulz-Schaeffer, 2007). The data also indicate an important role for the cell biology of the presynaptic terminal in the pathogenesis of PD. A model emerges where defects in pathways that regulate protein turnover at synapses and aggregated or dysfunctional proteins at synapses (e.g. α-Synuclein) both contribute to synaptic demise in PD. In this review, we discuss the mechanisms that synapses use to survey their proteome and we point out the many direct connections to pathways of PD. We propose that defects in the regulation of protein turnover pathways at synapses are a common feature in the disease. Synaptic decay in the pathology of Parkinson's disease Parkinson's disease is a neurodegenerative condition that affects over 6 million people worldwide. The disease not only results in typical motor symptoms, but also in several debilitating non-motor symptoms that are gaining attention (Chen et al, 2015). The disease slowly progresses and there is no cure, resulting in steep care costs. The motor symptoms in PD result from the degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons (DA), but the disease is more widespread and many other neurons in the brain also suffer (Visanji et al, 2013). Evidence suggests that synaptic decay in PD precedes neuronal demise, suggesting this is an early pathological event. At the time motor symptoms are manifest, about 30% of SNc and about 50–60% of the DA terminals are already lost (Scherman et al, 1989; Fearnley & Lees, 1991; Ma et al, 1997; Greffard et al, 2006; Beach et al, 2008; Cheng et al, 2010). Thus, at the onset of the disease (here taken as the occurrence of motor symptoms), the loss of DA synaptic terminals exceeds the loss of DA cell bodies. In paraffin-embedded tissue blots with Lewy body pathology, the majority of α-Synuclein aggregates accumulate at presynaptic terminals (Kramer & Schulz-Schaeffer, 2007) and additional neuroanatomical studies of post-mortem patient brain samples from familial PD cases support the idea that synaptic decay precedes neuronal death (Hornykiewicz, 1998; Cheng et al, 2010; Burke & O'Malley, 2013). These observations support a “dying back” hypothesis where synaptic demise, including presynaptic dysfunction, occurs before overt neuronal death. Much of the research in PD has concentrated on DA loss in the SNc (Hirsch et al, 1988). The loss of these neurons causes typical PD motor symptoms, and this correlates with axonal degeneration in nigrostriatal pathways (Kordower et al, 2013; Caminiti et al, 2017). The SNc DA neurons are extremely ramified, and it has been suggested this is one of the reasons these neurons degenerate while other types of neurons survive. The axon arborizations of SNc DA neurons can reach a total length of four and a half meters and give rise to more than two million synaptic contacts, all connected to one cell body (Bolam & Pissadaki, 2012). In comparison, DA neurons of the ventral tegmental area (VTA) have significantly fewer synapses (< 30,000) and they do not degenerate in the context of PD. The axonal compartment of SNc neurons is comparatively very large, and we speculate that such an extensive neuronal arbor would significantly rely on local protein quality control mechanisms. Alterations in the synaptic protein turnover machinery may therefore have a more profound effect in SNc neurons compared to their less ramified counterparts in the VTA, providing possible explanations why the SNc neurons are so vulnerable. SNc neurons are not the only ones affected, and several other neuronal subtypes also die or are dysfunctional in PD. These are not necessarily extremely ramified, suggesting that other parameters than “extreme neuronal morphology” may contribute to neuronal dysfunction in PD and additional work is needed to understand this “cell type specificity” in the context of neurodegenerative disease. Several genes implicated in PD encode proteins that are enriched at the presynaptic terminal. Mutations in these genes likely cause defects in synaptic mechanisms that (eventually) manifest as defects in neurotransmitter release. A straightforward model would be that such synaptic function defects eventually elicit synaptic and neuronal demise. There are indeed several examples where mutations in genes encoding presynaptic proteins that mediate neurotransmitter release also cause neurodegeneration. For example, mutations in DNAJC5 (encoding CSPα) cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL), a severe neurodegenerative condition (Benitez et al, 2011; Nosková et al, 2011). Also, CSPα knock-out mice and flies display neurodegeneration and activity-dependent loss of synaptic terminals (Fernández-Chacón et al, 2004; Garcia-Junco-Clemente et al, 2010). However, these data do not exclude roles of CSPα beyond its function in neurotransmission. Indeed, there is evidence that disproves a simple linear correlation between synaptic dysfunction and synaptic demise. The loss of essential presynaptic proteins, Munc13–1/2 or the SNARE synaptobrevin-2/VAMP2, very strongly blocks synaptic transmission, yet this does not cause neurodegeneration (Schoch et al, 2001; Varoqueaux et al, 2002; Peng et al, 2013). Conversely, the loss of other essential proteins that reside at the presynaptic terminal, Munc18-1 and the SNARE SNAP-25 (and CSPα), also blocks synaptic transmission and this does cause neurodegeneration (Santos et al, 2017). Here, the authors were able to draw a correlation with Golgi abnormalities: They observed such abnormalities in Munc18-1 and SNAP-25 loss of function animals, but not in Munc13–1/2 or synaptobrevin-2/VAMP2 loss-of-function animals (Santos et al, 2017). However, how Golgi abnormalities cause neurodegeneration is elusive, and Golgi abnormalities are not universal among animals with mutations in synaptic proteins associated with neurodegeneration (EndoA, Synj1, DNAJ6, CSPα, etc. see below). Nonetheless, these results do indicate that presynaptic proteins that regulate neurotransmitter release can have divergent roles beyond their function in synaptic transmission. In other words, mere defects in neurotransmitter release do not (entirely) explain synaptic degeneration. We will argue that also the proteins mutated in PD have functions in pathways other than their (indirect) role in the regulation of transmitter release. In particular, we will review how these proteins regulate protein or organellar homeostasis, often uniquely at synapses. This idea mostly stems from studies of genes causative to familial forms of PD (Burré et al, 2010; Nemani et al, 2010; Zimprich et al, 2011; Edvardson et al, 2012; Matta et al, 2012; Krebs et al, 2013; Quadri et al, 2013; Soukup et al, 2016; Vanhauwaert et al, 2017). However, given that α-Synuclein aggregates, a proxy for protein homeostasis defects, are observed both in familial and sporadic cases of PD, this idea is most likely also relevant to the sporadic cases of the disease. Mechanisms that control protein homeostasis at synapses Protein homeostasis is under the control of different cellular mechanisms, and in some cases, synapses have specific adaptations (Labbadia & Morimoto, 2015; Vijayan & Verstreken, 2017). Protein homeostasis encompasses the activity of chaperones that fold and refold proteins in an ATP-dependent manner. Some of these chaperones are abundant (Hsp90) and even enriched (Hsc70/HSPA8) at synapses (Wang et al, 2017). When refolding by chaperones is not possible, proteins can be turned over by degradation. Synaptic membrane proteins are endocytosed and sorted at endosomes to be trafficked to lysosomes. Different routes of endosomal sorting have been found in neurons, and at synapses, the synaptic GTPase-activating protein Skywalker/TBC1D24 and the small GTPase Rab35 are involved (Uytterhoeven et al, 2011; Fernandes et al, 2014; Fischer et al, 2016; Sheehan et al, 2016). In addition, proteins and organelles can be degraded by autophagy. There are various types of autophagy, but common to all is that proteins or organelles are delivered to the lysosome for degradation. In most cellular compartments, the ubiquitin–proteasome system also plays a prominent role, but this process does not seem to be responsible for the local turnover of the majority of presynaptic proteins (Hakim et al, 2016). Of all protein turnover pathways, autophagy has been most strongly implicated in PD. Below, we review the different types of autophagy (reviewed in Galluzzi et al, 2017) and how they are connected to the proteins mutated in this disease: In macroautophagy, a large vesicle invaginates as to engulf part of the cytoplasm and/or organelles by a double-membrane structure. This autophagosome fuses with the lysosome to degrade and recycle the contents. Autophagosomes were recently shown to form at presynaptic endings and to be transported back to the cell body (Hernandez et al, 2012; Maday & Holzbaur, 2014; Binotti et al, 2015; Soukup et al, 2016; Oerlundk et al, 2017; Vanhauwaert et al, 2017). Macroautophagy can be non-selective or selective. In selective macroautophagy-tagged organelles, e.g., mitochondria with ubiquitinated proteins on their outer membrane are engulfed and degraded (Pickrell & Youle, 2015; Yamano et al, 2016; Galluzzi et al, 2017). Several proteins implicated in PD are in direct control of macroautophagy at synapses and in macroautophagy of a specific organelle, the mitochondria (mitophagy). We discuss this in more detail below. During endosomal microautophagy and chaperone-mediated autophagy, the chaperone Hsc70/HSPA8 recognizes specific protein motifs (similar to KFERQ) and brings proteins with these motifs to the endosomal membrane. This function of Hsc70 is independent from its role as a protein-refolding chaperone (Uytterhoeven et al, 2015). At the endosomal membrane, targeted proteins are either directly translocated over the endosomal membrane by the LAMP2a pore complex (chaperone-mediated autophagy; Bandyopadhyay et al, 2008) or the endosomal membrane invaginates as to engulf the targets (endosomal microautophagy; Sahu et al, 2011; Uytterhoeven et al, 2015; Mukherjee et al, 2016). Interestingly, synaptic proteins are significantly enriched for this “KFERQ” recognition motif (Uytterhoeven et al, 2015), and proteins central to PD (α-Synuclein, LRRK2, Tau) also contain this motif (Cuervo et al, 2004; Wang et al, 2009; Orenstein et al, 2013). This indicates that Hsc70-mediated autophagy may be important for the turnover of synaptic proteins also in the context of PD. More direct connections between proteins that mediate Hsc70-mediated autophagy and PD are currently lacking, but the possibility exists to exploit this process to regulate the levels of these pathogenic proteins as discussed elsewhere (Kaushik & Cuervo, 2015). Macroautophagy and mitophagy The proteins encoded by several “PD genes” have specific and direct actions in the regulation of macroautophagy (LRRK2, Synj1, DNAJC6, PINK1, Parkin, etc. see below). These observations were made based on loss- and gain-of-function studies of these “PD genes” in genetic model organisms as well as using induced neurons derived from patients (iPS). In addition, variation in genes that encode core components of the autophagic machinery, the proteins Atg5 and Atg7, is reported risk factors for PD (Chen et al, 2013a, 2013b). Lastly, recent work also found that variation in the EndoA1 gene constitutes a risk factor for PD (Chang et al, 2017). We and others showed that EndoA plays a prominent role in synaptic autophagy in fruit flies and mice (Murdoch et al, 2016; Soukup et al, 2016). Together these studies suggest that there is a common underlying theme where several of the genetic factors associated with PD encode proteins that affect the process of macroautophagy (Plowey et al, 2008; Winslow et al, 2010; Sánchez-Danés et al, 2012; Bravo-San Pedro et al, 2013; Zavodszky et al, 2014). Macroautophagy has been extensively studied in yeast and mammalian cells. The key players involved in macroautophagy are also expressed in neurons, suggesting that the core macroautophagy pathway is also important in neurons (Bains et al, 2009; Wong et al, 2011; Krüger et al, 2012; Sánchez-Danés et al, 2012; Viscomi et al, 2012). The process of macroautophagy (and thus also mitophagy) in yeast cells and mammalian cells starts by inhibition of the mTOR complex 1 resulting in the activation of the Atg1/ULK1 complex. This leads to the translocation of multiprotein complexes like—phosphatidylinositol 3-kinase (Vps34)—to preautophagosomal membranes. An important next step is the generation of phosphatidylinositol 3-phosphate (PI(3)P)-rich membranes by Vps34. Binding of WD40 repeat domain phosphoinositide-interacting (WIPI) proteins to PI(3)P/PI(3,5)P2-rich membranes facilitates the elongation of the isolation membrane and LC3 lipidation on the fully formed autophagosome (Proikas-Cezanne et al, 2015). Elongation is dependent on several proteins: Atg5, Atg12, and Atg16 forming an E3-like ligase complex that specifically binds to proteins of the WIPI family. Next, the ubiquitin-like conjugating enzyme Atg3, together with Atg4 and Atg7, conjugates LC3/ATG8 to phosphatidylethanolamine (PE) on the mature autophagosome. Following elongation and maturation, the autophagosome fuses with the lysosome, a process mediated by SNAREs (soluble N-ethylmaleimide-sensitive factor activating protein receptors; Menzies et al, 2017). Macroautophagy is important for neuronal survival as the knock-out of essential autophagy genes (e.g. atg7) in flies and mice causes neuronal defects, including neurodegeneration (Komatsu et al, 2006; Juhász et al, 2007). The exact steps that occur downstream of defective macroautophagy leading to the death of a cell remain elusive. However, it is conceivable that both the accumulation of dysfunctional proteins and organelles and the lack of fresh biomolecules for the synthesis of new proteins contribute to the deregulation of cellular homeostasis. Furthermore, as detailed below, there are also synapse-specific adaptations to the process of macroautophagy and several lines of recent evidence indicate that this synapse-specific process of macroautophagy is disrupted by mutations in “PD genes”. Macroautophagy ends by the fusion with lysosomes, thus degrading the contents. Lysosomes have been implicated in maintaining synaptic homeostasis (Sambri et al, 2017), and lysosomal dysfunction has been repeatedly associated with neurodegeneration, also in the context of PD (Dehay et al, 2012; Dodson et al, 2012; Usenovic et al, 2012; Miura et al, 2014; Mazzulli et al, 2016). ATP13A2 and glucocerebrosidase regulate lysosomal function and autosomal-recessive mutations in ATP13A2 cause PD, while heterozygosity for GBA predisposes to PD (Aharon-Peretz et al, 2004). In fact, the restoration or (hyper-)acidification of lysosomes has been proposed as a therapeutic approach for PD. For example, acidic nanoparticles that promote the acidification of lysosomes are able to rescue lysosomal defects in ATP13A2-mutant cells and in glucocerebrosidase-mutant cells. Moreover, intracerebral injection of these particles even diminishes dopaminergic neuron loss in a PD toxin model (Bourdenx et al, 2016). Hence, autophagic dysfunction and lysosomal dysfunction, and thus defects in intracellular degradation pathways, are often seen disrupted in models of PD (and other forms of neurodegeneration). It is plausible that defects in lysosomal activity contribute to the accumulation of α-Synuclein that is aggregation prone and of other (dysfunctional) proteins (Williamson et al, 2010; Ganley et al, 2011; Korolchuk et al, 2011; Takáts et al, 2014). In this context, it is noteworthy that specific post-translational modifications in α-Synuclein are also further inhibiting the ability of this protein to be degraded at lysosomes, thus contributing to its own aggregation (Smith et al, 2005). What remains unexplained is how dysfunction in such broad processes such as lysosomal function or autophagy elicits defects in a number of defined cell types. In addition, it is not known why other aggregation-prone proteins besides α-Synuclein are not aggregating consistently in PD. Classical macroautophagy is non-selective and triggered by amino acid deprivation. In neurons, the process is also triggered by neuronal activity, indicating there are neuron-specific pathways that initiate the process (Soukup et al, 2016). Macroautophagy can also be selective when it is triggered by “tagged targets”, for example the ubiquitination of outer mitochondrial membrane proteins. In addition to the classical macroautophagy machinery, different proteins, including Pink1, Parkin, and Fbxo7, regulate the targeted macroautophagy of mitochondria or mitophagy (Narendra et al, 2008; Geisler et al, 2010; Vives-Bauza et al, 2010; Yamano et al, 2016). Autosomal-recessive mutations in the genes that encode these proteins cause PD (Lücking et al, 2000; Bonifati et al, 2005; Ibáñez et al, 2006). Defects in mitochondrial turnover would eventually lead to an accumulation of dysfunctional mitochondria, and dysfunctional mitochondria are also often observed in tissue from sporadic PD patients (Parker et al, 2008). In addition, the effects of specific toxins on mitochondria recapitulate features of PD in humans and animal models, thereby further underlining the connection between dysfunctional mitochondria and PD (Przedborski & Jackson-Lewis, 1998). Parkin is a cytoplasmic E3 ubiquitin ligase, while Pink1 is a kinase that regulates mitochondrial function and also phosphorylates Parkin and ubiquitin (Ziviani et al, 2010; Kondapalli et al, 2012; Shiba-Fukushima et al, 2012). Pink1-dependent Parkin phosphorylation results in the ubiquitination of target proteins, such as those at the surface of mitochondria, and this is a trigger for autophagosomes to engulf these “tagged” mitochondria (Ziviani et al, 2010; Glauser et al, 2011). Further details on this process can be found in these excellent reviews: (Pickrell & Youle, 2015; Yamano et al, 2016; Galluzzi et al, 2017). In the context of DA neuronal terminals, mitophagy may be a necessary mechanism to survey the mitochondria in the vast expanse of the neuronal arbor of these cells, as to maintain a proper energy supply or to buffer calcium at the extremities of these neurons. Indeed, an intricate mechanism that regulates the transport of neuronal mitochondria exists and is under the control of Miro, another protein that is also phosphorylated by Pink1 (Wang et al, 2011). Mitochondrial motility regulates mitochondrial autophagy: When mitochondria stop moving (when they are less functional), autophagy is induced (Ahrafi et al, 2014). It has however been difficult to observe mitophagy at synapses in neurons in vivo and the functional relevance of the process in relation to neuronal survival and neuronal function is also elusive. While it is conceivable that a chronic failure to remove mitochondrial debris will cause harm to the cellular and synaptic environment, it is important to note that Pink1, Parkin, and Fbxo7 have also mitophagy-independent functions. Pink1 and Fbxo7 regulate the activity of complex I of the electron transport chain (Gautier et al, 2008; Morais et al, 2009; Chan et al, 2011; Vos et al, 2012; Delgado-Camprubi e" @default.
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• W2885280818 date "2018-07-31" @default.
• W2885280818 modified "2023-10-16" @default.
• W2885280818 title "Parkinson's disease: convergence on synaptic homeostasis" @default.
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