Parkin- an E3 Ubiquitin Ligase with Multiple Substrates

rs Disea me se ei & h P z l a Sandebring and Cedazo-Mínguez A. J Alzheimers Dis Parkinsonism 2012, S10 A r k f Journal of

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a DOI: 10.4172/2161-0460.S10-002

m o J ISSN: 2161-0460 Alzheimer’s Disease & Parkinsonism

Review Article Open Access Parkin- An E3 Ubiquitin Ligase with Multiple Substrates Anna Sandebring* and Angel Cedazo-Mínguez Karolinska Institutet Department of NVS, KI-Alzheimer’s Disease Research Center, NOVUM floor 5, 141 57 Huddinge, Sweden

Abstract Parkinson’s disease is a common neurodegenerative disorder. The clinical symptoms arise from a substantial loss of dopaminergic neurons in substantia nigra pars compacta, which causes motor symptoms such as bradykinesia and tremor. Although the majority of PD cases are sporadic, there is a growing number of genes shown to be involved in causing parkinsonism that manifests with similar pathology to the idiopathic disease. The most common cause to autosomal recessive parkinson’s disease (ARPD) is mutations in the gene encoding for parkin- an E3 ubiquitin ligase with widespread functions in the cell. In this review we summarize the substrates identified for parkin and which functions these imply in the cell. Elucidating the mechanism of functions of these substrates may contribute with clues on which pathways to study further in Parkinson’s disease pathology.

Abbreviations: ARPD: Autosomal Recessive Parkinson Disease; implies that the unfolded protein response is involved in the pathogenic CDC-rel: Cell Division Control related protein; Drp1: Dynamin process ultimately leading to neuronal death [4]. related protein 1; EGFR: Epidermal Growth Factor Receptor; FBP1: The complex machinery of protein ubiquitylation engages the Far upstream binding element; HDAC4: Histone Deacetylase 4; Hsp70: activity of ligases; The E1 ligases are required to activate the small Heat shock protein 70; IBR: in between RING; Iκκγ: Inhibitor of kappa ubiquitin monomers in an ATP demanding process, followed by E2 B Kinase; KO: Knock-Out; LB: Lewy Body; Miro: Mitochondrial Rho; ligase conjugation to ubiquitin, which then works in conjunction with NF-κB: Nuclear Factor κB; Pael-R: Parkin associated endothelial the E3 ligase to transfer ubiquitin to the E3 ligase bound substrate. The receptor; PD: Parkinson Disease; PDCD2-1: Programmed cell death E3 ligase thereby facilitates the isopeptide bond between the substrate 2 isoform-1; PICK1: Protein Interacting with C-kinase 1; PLC: and ubiquitin. There are multiple shapes of ubiquitin chains, arising Phospholipase C; RanBP2: Ran Binding Protein 2; RING: Really from the linkage between crucial lysine residues within the ubiqutin Interesting New Gene; SNpc: Substantia Nigra pars compacta; TRAF2: monomer. The complexity in protein ubiquitylation is thereby due TNF-receptor Associated Factor 2; UBL: Ubiquitin-like; VDAC: to the ability of ubiqutin to generate a variety of different polymer Voltage Dependent Anion Channel conformations, having varying consequences for the target substrates. Parkinson’s Disease Ubiquitylation can lead to proteasomal degradation, but depending on the mediating ligases and the structure of the formed ubiquitin Parkinson’s disease (PD) is the most common neurodegenerative chain, targeted proteins can also undergo endocytosis and lysosomal motor disorder and is clinically diagnosed by bradykinesia, degradation, or translocate and participate in cellular signaling (for rigidity, resting tremor and postural instability. The disease is reviews on ubiquitylation, see [5,6]). The ubiquitin pathway has been neuropathologically characterized by substantial loss of dopaminergic implicated in the pathogenesis of several diseases, some of them of neurons in the substantia nigra pars compacta (SNpc) and the presence genetic origin, including neurodegenerative diseases such as PD, of α-synuclein positive inclusions, termed Lewy bodies (LB) (PD ataxia and Alzheimer’s disease (for review on the ubiquitin pathway in reviewed in [1]). neurodegeneration, see [7]). The discovery of genes involved in the development of parkinsonism Parkin is an E3 Ubiquitin Ligase has contributed immensely to the comprehension of disease pathogenesis. Although PD is mainly a sporadic disorder, studies The ARPD associated gene product parkin has E3 ubiqutin ligase during the last decades have identified predisposing genetic risk factors activity and is hence serving as a substrate recognition enzyme within and a direct link to 16 loci and 11 genes. A growing understanding the cell [8]. Parkin has an N-terminal ubiquitin-like (UBL) domain of the genomics behind PD is providing important tools for studying and two RING (really interesting new gene) domains, flanked by a disease related mechanisms. Autosomal Recessive Parkinson’s disease cysteine rich in between RING (IBR) domain near the C-terminus (ARPD) is caused by mutations in parkin, PTEN induced kinase-1 [9]. The RING domain E3 ligase family is the largest group ofE3 (PINK1) or DJ-1, where mutations in parkin are the most common (for ligases and is characterized by the binding of two zinc ions in a reviews on genetics behind PD, see [2,3]). histidine and cysteine rich motif of the RING finger domain resulting Parkin is an E3 ubiquitin ligase expressed in several organs, but abundantly in the brain including the SNpc. In this review, we go *Corresponding author: Anna Sandebring, Karolinska Institutet., Department of through the identified parkin substrates and give an overview of which NVS, KI-Alzheimer’s Disease Research Center, NOVUM, 141 57 Huddinge, Swe- den, Tel: +468 58 58 36 67; Fax: +468 58 58 83 80; E-mail: [email protected] cellular functions that are associated to their respective roles, and thereby plausibly involved in PD pathogenesis. Received march 19, 2012; Accepted May 07, 2012; Published May 09, 2012 Citation: Sandebring A, Cedazo-Mínguez A (2012) Parkin- An E3 Ubiquitin Protein Ubiquitylation Ligase with Multiple Substrates. J Alzheimers Dis Parkinsonism S10:002. doi:10.4172/2161-0460.S10-002 Post-translational modification by protein ubiquitylation is the most important proteolytic quality control system in the cell. Copyright: © 2012 Sandebring A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits Pathological ubiquitin positive inclusion bodies in brain material unrestricted use, distribution, and reproduction in any medium, provided the from patients suffering from PD or other neurodegenerative diseases, original author and source are credited.

J Alzheimers Dis Parkinsonism Neurodegenerative Disorders ISSN:2161-0460 JADP an open access journal Citation: Sandebring A, Cedazo- Mínguez A (2012) Parkin- An E3 Ubiquitin Ligase with Multiple Substrates. J Alzheimers Dis Parkinsonism S10:002. doi:10.4172/2161-0460.S10-002

Page 2 of 6 in a globular conformation. The role of RING domains is to recruit member of the PSD95/discs large/ZO-1 (PDZ) protein family, that ubiquitin conjugating enzymes, E2 ligases thereby bind to the E3 regulates trafficking of proteins and mediates the assembly of large ligase RING domain where the ubiqutin is discharged and conjugated protein complexes and PICK1 itself is a presynaptic protein known to to the substrate [10]. Over 100 parkin mutations, including exonic associate with channels and receptors. In line with this function, the rearrangements, point mutations and small deletions or insertions authors show that parkin overexpression abolishes the PICK1 mediated have been identified, which places parkin as the most common cause potentiation of Acid-sensing ion channel subunit 2a, suggesting that of ARPD [11]. parkin mediated mono-ubiquitylation deactivates PICK1. Knock down of parkin however enhance the excitatory effect from this Parkin mediated ubiquitylation has been shown to involve the channel, which may imply that ARPD involve excitotoxicity through a conjugation to the E2 ubiquitin carrier proteins UbcH7 and UbcH8, lack of PICK1 regulation. which are typically involved in K48-linked polyubiquitylation in order to promote proteasomal degradation, and to UbcH13, which mediate Ubiquitylation and subsequent regulation of the levels of non-degrading K63-linked polyubiquitylation [12-14]. Indeed, several polyglutamine proteins ataxin-2 and -3 has been associated to parkin of the identified parkin substrates do not accumulate in parkin knock E3 ligase activity [28,29]. Parkin protects from ataxin-2 mediated out (KO) mice, ARPD parkin or idiopathic PD human brain, supporting neurotoxicity and is involved also in the regulation of the normal protein the notion that parkin is able to mediate different types of ubiquitylation levels [28,29]. When polyglutamine repeats are mutated and expanded, [15-17]. Furthermore, parkin has auto– polyubiquitylating properties, Purkinje neurons degenerate resulting in spinocerebellar ataxia type allowing the protein itself to be degraded by the proteasome [18], as 2. As in PD, neurodegeneration resulting from polyglutamine repeats well as auto– monoubiquitylation and –multiple monoubiquitylating also involves the formation of protein inclusion. Thus, it is possible that activities in vitro [19,20]. Some of the identified mutations in the parkin participates in the clearance of misfolded proteins not only in gene encoding for parkin, have been shown to impair its E3 ubiquitin the PD affected regions, but also for other neurodegenerative diseases. ligase activity for several substrates [12,14,18]. In the sections below, we describe different cellular functions modulated by parkin via its Vesicular Dynamics substrates. A more prominent role for parkin in vesicle formation was presented Synaptic Proteins and Protein Aggregation when the synaptic vesicle-enriched septin GTPases cell division control related protein (CDCrel) -1 and -2a were identified as parkin substrates Since PD brain pathology involves the presence of protein [18,30]. Parkin mediated UbcH8 dependent polyubiquitylation aggregates via an accumulation of unfolded proteins, it has been resulted in 26S proteasomal degradation of CDCrel-1 and CDCrel-2a suggested that parkin has a role in avoiding the formation of such and both proteins were shown to accumulate in human parkin mutant complexes by ubiquitin mediated proteasomal degradation. In line ARPD brain. Septins are important for synaptic vesicle transport, with the idea that parkin influence the amount of protein aggregation fusion and recycling [31]. CDCrel-1 has been found to inhibit vesicle in the cell, the molecular chaperone heat-shock protein 70 (Hsp70) exocytosis by association to syntaxin [32]. A possibility is therefore is regulated through parkin mediated mono-ubiquitylation [16]. that parkin, via interaction with septins, may regulate the release of Consistent with a multiple mono-ubiquitylation of Hsp70, there was dopamine. Indeed, overexpression of CDCrel-1 in substantia nigra of no accumulation of this substrate in the insoluble fraction in brain rats induces dopaminergic neurodegeneration and a decline in striatal tissue from parkin deficient ARPD subjects. However idiopathic PD dopamine levels [33]. In Drosophila melanogaster, overexpressing the patients show increased levels of Hsp70 in the insoluble fractions and CDCrel-1 homologue septin4 induced age dependent dopaminergic decreased levels in the soluble fraction, which leaves the possibility that neurotoxicity [34]. Parkin has also been shown to ubiquitylate and Hsp70 is differently activated in sporadic PD brain compared to the healthy brain. How parkin influence Hsp70 function is not elucidated, promote the degradation of misfolded dopamine transporter, which but may influence its activity. resulted in a more effective dopamine uptake [35]. One of the main pathological hallmarks in PD is the presence In line with the idea that impaired vesicular dopamine release may of LB, and interestingly parkin has been shown to associate with LB be related to PD pathogenesis, yet another parkin substrate associated and further to interact with an O-glycosylated form of α-synuclein to vesicular trafficking and dynamics is SynaptotagminXI. Parkin and synphilin-1, both of which are abundant LB components [17,21]. ubiquitylation led to proteasomal degradation of synaptotagminXI. Furthermore, parkin protects against toxicity mediated by α-synuclein Accumulation of synaptotagminXI was found in the core of LB of over-expression [22] and promotes the formation of ubiquitin positive substantia nigra sections from sporadic PD patients, where also the inclusions when inhibiting the proteasome [23]. It has thus been other parkin substrates synphilin-1, p38 and far upstream binding proposed that LB formation is a protective response to toxic insults, element (FBP1) are found to accumulate [36-39]. rather than the primary cause to neuronal cell death, and that this Regulation of Genomic Translation and the Cell Cycle process requires parkin activity. This may explain why the brains of parkin ARPD patient generally lack LB pathology [24,25]. Apart from The parkin substrate p38 is a structural component ofthe being LB components, the physiological roles of α-synuclein and mammalian aminoacyl t-RNA synthetase complex, which are key synphilin-1 are not fully elucidated. However, since both proteins are enzymes in the translation of the genetic code. Parkin protected from enriched in presynaptic terminals, they have been suggested to play p38 overexpression induced toxicity by promoting the formation a role in synaptic function. In fact, synphilin-1 associates to synaptic of cellular inclusions [36]. Both p38 and FBP1 were also found to vesicles and this interaction appears to be modulated by α-synuclein accumulate in brain homogenates from parkin KO mice. FBP1 [26]. is an activator of the proto-oncogene c-myc. Ubiquitylation and Another pre-synaptic protein is Protein interacting with C-kinase proteasomal degradation of FBP1 is promoted by p38 and similarly 1 (PICK1) which is mono-ubiquitylated by parkin [27]. PICK1 is a FBP1 upregulates the expression of p38, which is toxic to cells [40].

J Alzheimers Dis Parkinsonism Neurodegenerative Disorders ISSN:2161-0460 JADP an open access journal Citation: Sandebring A, Cedazo-Mínguez A (2012) Parkin- An E3 Ubiquitin Ligase with Multiple Substrates. J Alzheimers Dis Parkinsonism S10:002. doi:10.4172/2161-0460.S10-002

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Both proteins thus appear in the same pathogenic, parkin regulated activating the nuclear factor-κB (NF-κB) signaling cascade [52]. This pathway. is achieved by non-proteasomal poly-ubiquitylation of the NF-κB signaling molecules Iκκγ and TRAF2. NF-κB signaling regulate genes A ubiquitin ligase complex involving parkin together with hSel-10 related to cell death, differentiation and immunity and is believed to have and Cul1 was found to ubiquitinate and regulate the levels of the cyclin consequences for both neuroprotection and synaptic plasticity [53]. dependent kinase-2 regulatory subunit cyclin E [41]. Cyclin E levels accumulated in nigral regions from both ARPD and sporadic PD brain Parkin associated endothelial receptor (Pael-R) is a substrate for material and the authors further show that parkin was protective to which parkin has been shown to mediate degradative poly-ubiquitylation neuronal apoptosis induced by kainate excitotoxicity. Glutamatergic [54]. The G-protein coupled receptor Pael-R is selectively expressed neurotoxicity is a feature that may be related to PD pathology and in in substantia nigra, accumulates in the endoplasmic reticulum and which cyclin E has previously been reported to play a role [42]. induces unfolded protein stress in cells when parkin was inactive. Levels of Pael-R are also increased in the insoluble fractions from ARPD brain Associated to cdk2/cyclin E is the oncogene β-catenin, a component homogenates, suggesting that Pael-R is an in vivo parkin substrate. in the Wnt signaling pathway which promotes cell proliferation [43]. Analysis from Pael-R KO and transgenic mice suggests that the Pael-R Intriguingly, parkin has been shown to associate to and regulate the is regulating the dopaminergic content in substantia nigra neurons. levels of β-catenin [44]. Parkin KO mice accumulate β-catenin and Also, neurons of Pael-R transgenic mice were more susceptible to PD stabilizing β-catenin in cells resulted in an increase in cyclin E and related toxins-induced cell death, by a mechanism involving unfolded associated cell death. protein stress response [55]. Furthermore, excessive Pael-R expression The E3 SUMO ligase Ran binding protein 2 (RanBP2) regulates in parkin KO mice induced cell death [56]. Pael-R is a homologue protein shuttling between nucleus and cytosol by localizing in the to endothelin receptor type B, which has been shown to regulate cytoplasmic filament of the nuclear pore complex. Proteasomal phospholipase (PLC) activity [43] and subsequently the mobilization degradation of RanBP2 is promoted by parkin ubiquitylation. A of intracellular Ca2+ and facilitation of Ca2+ influxes [47]. We identified downstream effect from parkin ubiquitylation was a decreased PLCγ1 as a parkin substrate [57], and showed that parkin mutations or sumolyation of the RanBP2 substrate histone deacetylase 4 (HDAC4), siRNA knock-down resulted in increased PLC activity and enhanced which repress gene transcription by chromatin condensation [45]. intracellular calcium levels, sensitizing cells to toxic insults [58]. Given the role of Pael-R in the induction of PLC activity, it is possible that Programmed cell death 2 isoform-1 (PDCD2-1) is a protein parkin is mediating regulatory ubiquitylation of several substrates involved in cell death, inflammation and proliferation. Parkin mediates related to the same signaling pathway. Indeed, increased cytosolic the proteasome dependent ubiquitylation of PDCD2-1 and increased calcium level is suggested to participate in PD pathogenesis [59]. level of this substrate is found in substantia nigra from ARPD and sporadic PD subjects [46]. PLCγ1 is activated through binding to the epidermal growth factor receptor (EGF-R), for which internalization is mediated by another Thus, parkin is regulating cellular proliferation by association with parkin substrate, epidermal growth factor receptor substrate 15 (Eps15) several important cell cycle regulatory molecules. Indeed parkin has [60]. Parkin regulates Eps15 activity by proteasome independent been shown to exhibit tumour suppressor effects [23,47]. The link mono-ubiquitylation, which results in decreased internalization of the between cancer and parkin may also be related to the destabilization of EGF-R. EGF treatment stimulates the binding of parkin to Eps15 and cell proliferating mechanisms through the substrates mentioned above. to the EGF-R. Inactivation of parkin consequently results in increased Stability of Cytoskeletal Components EGF-R internalization and degradation and in reduced activity the pro- survival PI3K/Akt signaling pathway. A putative role for parkin is in the quality control of the cellular cytoskeleton. This is based on the finding that parkin ubiquitinates Interestingly, the parkin substrate β-catenin [44] (discussed in a and regulates the levels of α- and β- tubulins [48]. To ensure accurate section above) is downstream of the EGF mediated PI3K/Akt signaling cytoskeletal dynamics, the levels of cytoskeletal components are pathway, where β-catenin is phosphorylated by pAkt regulated GSK3β tightly controlled in an autoregulated manner. In animal cells, a feed [61]. Figure 1 summarizes the parkin substrates related to PLC and EGF-R signaling. back mechanism regulates the stability of tubulin mRNA depending on the cellular concentration of tubulin heterodimers [49]. Whether impairment in this process is influencing disease pathogenesis in ARPD patients remains to be answered, yet parkin and α- tubulin EGF-R Pael-R has been shown to accumulate in the insoluble fractions from cells overexpressing α-synuclein and in LB disease brains [50].

The cytoskeletal component actin can form aggregates by the Eps15 PL C γ1 activity of cofilin. Cofilin phosphorylation is regulated by Lim Kinase Ub Ub 1, which is another parkin substrate [51]. Parkin ubiquitylation of Ub ParKin ParKin Lim Kinase 1 decreases cofilin activity and is thereby stabilizing the ParKin structure of actin, reversibly Lim Kinase 1 also regulate the E3 ligase activity of parkin. The authors further show that Lim Kinase 1 forms Endocytosis a complex together with Hsp70, parkin and CHIP, where CHIP has a stabilizing role. Figure 1: Parkin substrates related to EGF-R and PLC signaling. Parkin pre vents the endocytosis of the EGF-R by mono-ubiquitinating Eps15. PLCγ1 is activated by binding to the EGF-R and parkin ubiquitinates and regulates the Cell Survival Related Signaling degradation of PLCγ1. Pael-R is activating PLC and its degradation is regu Parkin has been shown to exert its neuroprotective capacity by lated by parkin ubiquitylation.

J Alzheimers Dis Parkinsonism Neurodegenerative Disorders ISSN:2161-0460 JADP an open access journal Citation: Sandebring A, Cedazo-Mínguez A (2012) Parkin- An E3 Ubiquitin Ligase with Multiple Substrates. J Alzheimers Dis Parkinsonism S10:002. doi:10.4172/2161-0460.S10-002

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Substrate Physiological function Ub. Degradation Ref Hsp70 Molecular chaperone Mono No [16] α-Sp22 Lewy body component Poly Yes [17] Synphilin-1 Interact with α-synuclein Poly No [21] PICK1 Synaptic scaffolding protein Mono No [27] Ataxin-3 Polyglutamine Poly Yes [29] Ataxin-2 Polyglutamine Poly Yes [28] CDCrel-1 Synaptic vesicle associated GTPase Poly Yes [18] CDCrel-2a Synaptic vesicle associated GTPase Poly Yes [30] SynaptotagminXI Membrane trafficking protein Poly Yes [37] p38 Aminoacyl t-RNA synthetase cofactor Poly Yes [36] FBP1 Regulates c-myc mRNA Yes Yes [38] Cyclin E Cell cycle regulating protein Poly Yes [41] β-catenin Component in Wnt signaling Unknown Yes [44] RanBP2 Interact with nuclear pore complex Poly Yes [45] PDCD2-1 Involved in apoptosis, inflammation and proliferation Poly Yes [46] α/β-tubulin Cytoskeletal components Unknown Yes [48] Lim Kinase 1 Phosphorylates cofilin Poly Yes [51] Iκκγ Component in NFκB signaling Poly No [52] TRAF2 Component in NFκB signaling Yes No [52] Pael-R G-protein coupled receptor Poly Yes [54] PLCγ1 Hydrolyzes lipids Unknown Yes [57] Eps15 Internalizes EGF-R Mono No [60] VDAC Mitochondrial ion channel Poly No [63] Bcl-2 Anti-apoptotic protein Mono No [15] Mitofusin-1/-2 Mitochondrial fusion protein Poly Yes [70] Drp1 Mitochondrial fission protein Poly Yes [71] Miro Mitochondrial anchor protein Unknown Yes [72] Table 1: Parkin substrates (Ub: ubiquitylation by parkin).

Mitochondrial Morphology, Motility and Mitophagy transport). Mitochondrial Rho (Miro) GTPase is together with Milton forming a complex with kinesin to link mitochondria to the Recent studies show that parkin has a key role in the process of microtubuli. It was lately discovered that overexpression of parkin, in mitophagy- the clearance of dysfunctional mitochondria [62] by concert with PINK1, could halt mitochondrial motility and this finding associating to the mitochondrial membrane upon toxic challenge. was further linked to parkin mediated proteasomal degradation of Miro A couple of parkin substrates has so far been identified to be crucial upon mitochondrial depolarization [72]. Interestingely, Mitofusin and for successful mitophagy; K27-linked poly-ubiquitylation of VDAC Miro also interact [73], which may reflect that their parkin dependent [63] and mono-ubiquitylation of the anti-apoptotic protein Bcl-2. degradation are both pieces from the same puzzle. Parkin mediated ubiquitylation of Bcl-2 enhanced Bcl-2 stability and inhibited autophagy [15]. Mitochondrial clearance is tightly Conclusions and Perspectives connected to mitochondrial morphology, which is in turn regulated by mitochondrial fusion and fission proteins. In recent years it has become The studies of monogenic forms of PD have generated new insights clear that all ARPD related proteins exhibits important functions of the disease pathogenesis. The list of substrates for parkin is constantly for maintaining mitochondrial membrane dynamics, where PINK1 growing and judging from their spread cellular functions, it appears that acts upstream of parkin [64-69]. When it comes to parkin substrates parkin has a large impact on cellular physiology. Protein misfolding and mitochondrial dynamics, it was recently shown that parkin and aggregates are important features in PD pathology, where the ubiquitylates the outer mitochondrial membrane fusion proteins proteasome dependent polyubiquitylation mediated by parkin may Mitofusin-1 and -2, leading to their degradation in both a proteasome- be an important feature. More recently parkin has also been shown and a AAA+ ATPase p97-dependent manner [70]. The authors further to mediate non-proteasomal ubiquitylation and is thereby regulating suggests that parkin mediated degradation of mitofusins is selective to endocytosis or protein activity. Recent data points out similarities in dysfunctional mitochondria and thus promoting these organelles to functions between parkin and the other ARPD causative gene products mitophagy. Parkin also mediates the proteasomal degradation of the PTEN induced kinase-1 (PINK1) and DJ-1, especially on mitochondrial mitochondrial fission protein dynamin related protein-1 (Drp1) [71] morphology and mitophagy [74,75]. Some studies even suggest that where decreased parkin expression lead to increased Drp1 levels and parkin, PINK1 and DJ-1 form a complex [76]. Therefore it would be of mitochondrial fragmentation as a consequence. interest to further study how the identified parkin substrates behave in A neuron specific challenge is that mitochondria and other a PINK1 or DJ-1 mutant background. Finding out if there are pathways organelles must be transported along axons in order to supply the or functions that are affected in all ARPD mutant gene products may synapse with energy. Failure of transport may be detrimental to the help to dissect the more important substrates on the list and thus to cell. The transport of mitochondria is obtained via the linkage to motor identify neurodegenerative mechanisms of importance for PD which proteins kinesin (for anterograde transport) and dynein (for retrograde may be of value for the development of future drug targets.

J Alzheimers Dis Parkinsonism Neurodegenerative Disorders ISSN:2161-0460 JADP an open access journal Citation: Sandebring A, Cedazo-Mínguez A (2012) Parkin- An E3 Ubiquitin Ligase with Multiple Substrates. J Alzheimers Dis Parkinsonism S10:002. doi:10.4172/2161-0460.S10-002

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J Alzheimers Dis Parkinsonism Neurodegenerative Disorders ISSN:2161-0460 JADP an open access journal Citation: Sandebring A, Cedazo-Mínguez A (2012) Parkin- An E3 Ubiquitin Ligase with Multiple Substrates. J Alzheimers Dis Parkinsonism S10:002. doi:10.4172/2161-0460.S10-002

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This article was originally published in a special issue, Neurodegenerative Disorders handled by Editor(s). Dr. Jesus Avila, Universidad Autonoma de Madrid, Spain.

J Alzheimers Dis Parkinsonism Neurodegenerative Disorders ISSN:2161-0460 JADP an open access journal