Rab Proteins in Mitophagy: History
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Contributor:
Adeena Shafique
,
Martina Brughera
,
Marta Lualdi
,
Tiziana Alberio

Mitochondrial dysfunction and vesicular trafficking alterations have been implicated in the pathogenesis of several neurodegenerative diseases. It has become clear that pathogenetic pathways leading to neurodegeneration are often interconnected. Indeed, growing evidence suggests a concerted contribution of impaired mitophagy and vesicles formation in the dysregulation of neuronal homeostasis, contributing to neuronal cell death. Among the molecular factors involved in the trafficking of vesicles, Ras analog in brain (Rab) proteins seem to play a central role in mitochondrial quality checking and disposal through both canonical PINK1/Parkin-mediated mitophagy and novel alternative pathways. In turn, the lack of proper elimination of dysfunctional mitochondria has emerged as a possible causative/early event in some neurodegenerative diseases.

  • vesicular trafficking
  • neurodegeneration
  • Ras analog in brain (Rab)
  • mitophagy

1. Introduction

Vesicular trafficking alterations have been implicated in the pathogenesis of several neurodegenerative diseases (NDs) as likely early events [1][2]. Two main branches of vesicle trafficking exist in neuronal cells: the canonical shuttling of cellular components and the mobilization of synaptic vesicles. Both processes are tightly regulated and orchestrated by multiprotein complexes. Their malfunction causes profound alterations in cellular homeostasis.
As for canonical vesicle trafficking, the three central pathways are: (i) the secretory pathway, (ii) the endocytic pathway, and (iii) specialized/organelle-specific vesicular transports [3]. The secretory pathway, through which proteins and lipids move from the ER through the Golgi to the extracellular environment, involves two main processes, namely, the anterograde (from ER to Golgi) and the retrograde (from Golgi to ER) transports, which are mediated by COPII and COPI coatomers, respectively. The endocytic pathway, in which several cargos can be internalized by cells, involves the formation of early and late endosomes, which eventually fuse with lysosomes; in this process, several proteins assist vesicle formation, e.g., clathrin, caveolins, adaptors, GTPase dynamins, Ras analog in brain (Rab) proteins, and vacuolar protein sorting (VPS) proteins. Eventually, several specialized vesicle transports have been recently discovered, which mirror the high dynamism and social behavior of cellular organelles [4]. The endoplasmic reticulum (ER), Golgi apparatus, lysosomes, peroxisomes, and mitochondria are known to physically interact and exchange components thanks to both contact sites and vesicles formation; this allows organelles to modulate specific cellular functions, pathways, and metabolism. As an example, mitochondria are known to communicate with the ER, Golgi apparatus, lysosomes, lipid droplets, peroxisomes, and melanosomes [5]. The contact sites between mitochondria and the ER (i.e., mitochondria-associated membranes, MAMs) are important hubs for lipid trafficking, Ca2+ homeostasis, ER stress, apoptosis, and macroautophagy. On the other hand, the mitochondria-lysosome axis leads to the formation of vesicles of mitochondrial origin (i.e., mitochondria-derived vesicles, MDVs), whose generation and release are central to the disposal of defective components without triggering the mitophagic process. However, the content of MDVs is still mostly unknown; some components seem to play a role in the activation of inflammatory processes and are being investigated as candidate plasma biomarkers for NDs [6][7].
As for synaptic vesicles, neuronal synapses are specialized subcellular compartments, where the cycles of exocytosis and endocytosis are regulated by a complex molecular machinery, including several proteins, e.g., SNAREs, synaptotagmin, synaptophysin, and some small GTPases belonging to the Rab family (mainly Rab3, Rab5, and Rab27) [8]. Synaptic vesicles are classified in pools based on their function: they can either be part of the reserve pool or be involved in active exo- and endocytotic cycles. The mobilization of vesicles from one pool to another is an ATP-dependent process, fueled by the mitochondria that are resident in the synapses. Thus, synapses which lack mitochondria display marked defects in vesicular trafficking that are mirrored by deficits in neuronal functionality [9]. This further supports a clear link between mitochondrial dysfunction, which is a crucial pathogenetic process in many NDs, and defects in vesicular trafficking.
Mitochondria are central organelles in all cell types, being responsible for energy production in the form of ATP, the biosynthesis of amino acids and steroids, β-oxidation of fatty acids, the maintenance of cytosolic calcium homeostasis, the production and modulation of reactive oxygen species (ROS), and the triggering of the apoptotic cell death program. Moreover, they are dynamic organelles that are transported on cytoskeletal proteins and organized in networks, which are continuously remodeled by fusion and fission events [10]. This allows for both the exchange of mitochondrial components and the elimination of damaged parts to maintain a functional pool of healthy mitochondria. Damaged mitochondria must be disposed of through a macroautophagic pathway called mitophagy. Canonical mitophagy involves PTEN-induced kinase 1 (PINK1) and Parkin proteins, which are responsible for the recruitment of the molecular machinery that guides the formation of the autophagosome and the subsequent fusion with lysosomes [11]. When mitophagy is hampered, dysfunctional mitochondria accumulate within cells, thus increasing ROS concentration and oxidative load in general. Considering the huge energy demand and the terminally differentiated state of neuronal cells, it appears evident that any alterations to physiological mitochondrial homeostasis can have devastating effects on neuronal survival.
Nowadays, there is convincing evidence of impaired mitochondrial function as a cause rather than a consequence of the neurodegenerative process in several NDs, such as Alzheimer’s disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD). For instance, in the frame of PD etiopathology the vast majority of genetic PD-related loci are associated with mitochondria, and aberrant mitochondrial function has emerged as central also in sporadic PD [12]. Recently, vesicular trafficking defects have also been highlighted as important pathogenetic factors [13]. Alpha-synuclein, the major component of toxic protein aggregates in PD, has been shown to directly bind the SNARE protein VAMP2 and to be critical for the proper assembly of the SNARE complex [14]. LRRK2 protein, whose gene mutation is linked to autosomal dominant inherited familial PD, has been demonstrated to co-localize with Rab5 on endocytic vesicles [15] and to be the kinase of several Rab proteins [16][17]. The substrate repertoire of Parkin, which acts as an E3 ubiquitin ligase and is found to be mutated in autosomal recessive juvenile PD, includes several proteins involved in vesicular trafficking, such as Synphilin1 and Synaptotagmin XI [18]. In addition, recent genome-wide association studies (GWASs) have proposed new loci associated with an increased risk of PD, which encode proteins involved in vesicular trafficking, such as VPS35, Synaptojanin1, VPS13C, Rab39B, Rab7L1/Rab29, and Synaptotagmin XI [13][19][20].

2. Mitochondrial Dynamics Altered in Neurodegeneration

Mitochondria are double-membraned organelles strictly involved in the regulation of cellular homeostasis and metabolism. Among the most common known functions, such as ATP production, ion homeostasis, biosynthesis of precursors for macromolecules, and management of toxic metabolic by-products, mitochondria are emerging as being more and more relevant to regulating signaling pathways and cellular stress responses [21]. They are interconnected entities that constitute branched tubular networks, which are not fixed structures; rather, they are highly dynamic and their shape is deeply affected by perturbations to cellular functions [22].
Mitochondrial dynamics collectively refer to all the processes involved in the morphological changes of the mitochondrial network, and they include fusion, fission, mitophagy, and mitochondrial transport [23]. These processes are deeply interrelated and part of the quality control of mitochondrial organelles. The fine tuning of fusion and fission dynamic transitions is orchestrated mainly by the dynamin-related family of large GTPases, and the resulting balance between the two processes is responsible for the number and size of mitochondria [10]. Mitophagy is the process that allows dysfunctional mitochondria to be degraded. It can be triggered by different stimuli and completed by distinct pathways [24]. The altered balance of the abovementioned processes often results in the intracellular accumulation of dysfunctional organelles, thus contributing to the onset and progression of several NDs.

3. Rab Proteins at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration

Rab proteins represent the largest family of Ras-like GTPases. They are largely distributed in eukaryotic cells with more than 70 members identified in mammals and 11 homologs in budding yeast [25][26]. Rab proteins exist within cells as molecular switches and shift between an active GTP-bound form, which associates with intracellular membranes, and an inactive GDP-bound conformation, which is present in the cytosol. These small GTPases require prenylation at their C-terminal cysteine residues to associate with membranes. This process is aided by geranylgeranyl transferases (GGTs) and Rab escort proteins (REPs). When membrane-bound, Rab proteins are activated by the exchange of GDP with GTP, and this is catalyzed by guanine nucleotide exchange factors (GEFs). In their active state, Rab proteins perform a myriad of functions, including vesicular budding, trafficking, and fusion with target membranes. On delivering cargo, Rabs undergo hydrolysis of the bound GTP to GDP with the help of GTPase-activating proteins (GAPs). In the inactive state, Rab proteins are retrieved and sequestered in the cytosol by GDP dissociation-inhibitor (GDI) proteins [27][28].
Rab proteins have been linked to multiple diseases, including NDs, cancer, and diabetes [29]. Among NDs, Rab proteins have been linked to dementia, AD, PD, HD, and ALS. In humans, 24 Rab proteins were found to be involved in the central nervous system [30], where many of them perform specialized neuronal functions [31]. More recently, the involvement of altered vesicle trafficking, particularly that which is Rab protein-mediated, has been highlighted in ND pathobiology. This finding has also proven to be a challenge, as studies are endeavoring to determine whether Rab proteins are causes or effects in the pathogenesis of NDs.
As Rab proteins are master regulators of vesicle trafficking, it is not surprising that they are emerging as key players in the molecular pathways of PD through a complex interplay with several PD-related genes. The question to be addressed is which Rab proteins are relevant to the mechanisms involved in PD, and to what extent. The most striking evidence of Rab proteins’ involvement came from the discovery of genetic alterations in familial forms of PD. Rab39B has a high brain-specific and exclusively neuron-specific expression [32]. Mutations in Rab39B resulted in a complete loss of protein expression and function and X-linked intellectual disability with early-onset PD [33]. Moreover, in Rab39B knockout mice, deficiency in Rab39B led to impaired learning and memory and impaired basal autophagic flux [34]. Another Rab gene, Rab29 (Rab7L1), has emerged as a leading candidate for sporadic PD, being one of the five genes that belongs to the PARK16 locus. Its role in PD pathogenesis is not completely understood; however, several studies have pointed to its upstream regulatory role in relation to LRRK2, whereby Rab29 increases LRRK2 activity and its localization to the trans-Golgi network [16][35][36]. LRRK2 mutations are the most common causes of familial PD and are also implicated in sporadic PD. The link between LRRK2 and Rab proteins came from the discovery that LRRK2 phosphorylates a wide subset of them, including Rab1A, Rab1B, Rab3, Rab5, Rab8A, Rab10, Rab12, Rab29, Rab35, and Rab43 [36]. All pathological LRRK2 mutations lead to hyperactivation of the protein, followed by abnormal Rab phosphorylation, which is abrogated upon pharmacological inhibition of LRRK2. Indeed, clinical trials are currently ongoing using small molecules as inhibitors of LRRK2 kinase activity, with potential beneficial effects in both familial and sporadic PD cases. As a downstream effect of LRRK2 inhibition, the restoration of physiological activity of Rab proteins is crucial to explanations of the therapeutic effects of these drugs [37]. An integrated omics analysis revealed dysregulation of the endocytic pathway in iPSC-derived dopaminergic neurons carrying the G2019S mutation in LRRK2. This dysregulation could be due to changes in the activity of several Rab proteins, including Rab5B, Rab7, and Rab10 [38].
Several studies have also established the role of Rab proteins in modulating α-synuclein biology in different model systems. Rab5, an early endosomal protein, is integral to the biogenesis of early endosomes [39]. It has been reported in the endocytosis of α-synuclein leading to neuronal death [40]. Another endosomal Rab, Rab7, was shown to clear α-synuclein aggregates. In HEK293 cells and Drosophila melanogaster, overexpression of Rab7 led to the clearance of α-synuclein aggregates and reduced cell death, thereby showing its protective role. This protective effect was specific to Rab7, as Rab5, Rab9, and Rab23 failed to rescue the phenotype [41]. Moreover, over-expressed α-synuclein was found to interact with dynein and induced an increase in the levels of GTP-bound Rab5 and Rab7 [42]. Eventually, overexpression of Rab11, physiologically involved in endosomal recycling, has also been shown to regulate α-synuclein dynamics in Drosophila models of α-synuclein toxicity [43].
As mitochondrial dysfunction makes a clear contribution to NDs, particularly PD, it is imperative to understand the pathways that regulate mitochondrial health. It is quite evident that mitochondrial quality-control pathways involve an intricate network of proteins and pathways, many of which have not been clearly understood and identified yet. For quite some time, macroautophagy was believed to be the only mechanism for degrading organelles, including mitochondria. Many studies are building up evidence that brings Rab proteins to the forefront in the clearing of damaged mitochondria via different pathways. Studies have also reported that alterations to Rab proteins related to their phosphorylation states, expression levels, and localization can lead to defects in mitophagy.

This entry is adapted from the peer-reviewed paper 10.3390/ijms24076268

References

  1. Wang, X.; Huang, T.; Bu, G.; Xu, H. Dysregulation of Protein Trafficking in Neurodegeneration. Mol. Neurodegener. 2014, 9, 31.
  2. Kiral, F.R.; Kohrs, F.E.; Jin, E.J.; Hiesinger, P.R. Rab GTPases and Membrane Trafficking in Neurodegeneration. Curr. Biol. 2018, 28, R471–R486.
  3. Blackstone, C.; Elwood, F.; Plun-Favreau, H.; Lewis, P.A. Vesicle Trafficking and Pathways to Neurodegeneration. Mol. Neurodegener. 2021, 16, 56.
  4. Silva, B.S.C.; DiGiovanni, L.; Kumar, R.; Carmichael, R.E.; Kim, P.K.; Schrader, M. Maintaining Social Contacts: The Physiological Relevance of Organelle Interactions. Biochim. Biophys. Acta BBA Mol. Cell Res. 2020, 1867, 118800.
  5. Gordaliza-Alaguero, I.; Cantó, C.; Zorzano, A. Metabolic Implications of Organelle–Mitochondria Communication. EMBO Rep. 2019, 20, e47928.
  6. Picca, A.; Guerra, F.; Calvani, R.; Coelho-Junior, H.J.; Bossola, M.; Landi, F.; Bernabei, R.; Bucci, C.; Marzetti, E. Generation and Release of Mitochondrial-Derived Vesicles in Health, Aging and Disease. J. Clin. Med. 2020, 9, 1440.
  7. Picca, A.; Guerra, F.; Calvani, R.; Bucci, C.; Lo Monaco, M.R.; Bentivoglio, A.R.; Landi, F.; Bernabei, R.; Marzetti, E. Mitochondrial-Derived Vesicles as Candidate Biomarkers in Parkinson’s Disease: Rationale, Design and Methods of the EXosomes in PArkiNson Disease (EXPAND) Study. Int. J. Mol. Sci. 2019, 20, 2373.
  8. Augustine, G.J.; Burns, M.E.; DeBello, W.M.; Hilfiker, S.; Morgan, J.R.; Schweizer, F.E.; Tokumaru, H.; Umayahara, K. Proteins Involved in Synaptic Vesicle Trafficking. J. Physiol. 1999, 520, 33–41.
  9. Vos, M.; Lauwers, E.; Verstreken, P. Synaptic Mitochondria in Synaptic Transmission and Organization of Vesicle Pools in Health and Disease. Front. Synaptic Neurosci. 2010, 2, 139.
  10. Tilokani, L.; Nagashima, S.; Paupe, V.; Prudent, J. Mitochondrial Dynamics: Overview of Molecular Mechanisms. Essays Biochem. 2018, 62, 341–360.
  11. Ma, K.; Chen, G.; Li, W.; Kepp, O.; Zhu, Y.; Chen, Q. Mitophagy, Mitochondrial Homeostasis, and Cell Fate. Front. Cell Dev. Biol. 2020, 8, 467.
  12. Park, J.-S.; Davis, R.L.; Sue, C.M. Mitochondrial Dysfunction in Parkinson’s Disease: New Mechanistic Insights and Therapeutic Perspectives. Curr. Neurol. Neurosci. Rep. 2018, 18, 21.
  13. Ebanks, K.; Lewis, P.A.; Bandopadhyay, R. Vesicular Dysfunction and the Pathogenesis of Parkinson’s Disease: Clues From Genetic Studies. Front. Neurosci. 2020, 13, 1381.
  14. Burré, J.; Sharma, M.; Tsetsenis, T.; Buchman, V.; Etherton, M.; Südhof, T.C. α-Synuclein Promotes SNARE-Complex Assembly in Vivo and in Vitro. Science 2010, 329, 1663–1667.
  15. Shin, N.; Jeong, H.; Kwon, J.; Heo, H.Y.; Kwon, J.J.; Yun, H.J.; Kim, C.-H.; Han, B.S.; Tong, Y.; Shen, J.; et al. LRRK2 Regulates Synaptic Vesicle Endocytosis. Exp. Cell Res. 2008, 314, 2055–2065.
  16. Liu, Z.; Bryant, N.; Kumaran, R.; Beilina, A.; Abeliovich, A.; Cookson, M.R.; West, A.B. LRRK2 Phosphorylates Membrane-Bound Rabs and Is Activated by GTP-Bound Rab7L1 to Promote Recruitment to the Trans-Golgi Network. Hum. Mol. Genet. 2018, 27, 385–395.
  17. Singh, P.K.; Muqit, M.M.K. Parkinson’s: A Disease of Aberrant Vesicle Trafficking. Annu. Rev. Cell Dev. Biol. 2020, 36, 237–264.
  18. Chung, K.K.; Zhang, Y.; Lim, K.L.; Tanaka, Y.; Huang, H.; Gao, J.; Ross, C.A.; Dawson, V.L.; Dawson, T.M. Parkin Ubiquitinates the Alpha-Synuclein-Interacting Protein, Synphilin-1: Implications for Lewy-Body Formation in Parkinson Disease. Nat. Med. 2001, 7, 1144–1150.
  19. Kia, D.A.; Zhang, D.; Guelfi, S.; Manzoni, C.; Hubbard, L.; United Kingdom Brain Expression Consortium (UKBEC); International Parkinson’s Disease Genomics Consortium (IPDGC); Reynolds, R.H.; Botía, J.; Ryten, M.; et al. Integration of EQTL and Parkinson’s Disease GWAS Data Implicates 11 Disease Genes. bioRxiv 2019, 10, 627216.
  20. Nalls, M.A.; Blauwendraat, C.; Vallerga, C.L.; Heilbron, K.; Bandres-Ciga, S.; Chang, D.; Tan, M.; Kia, D.A.; Noyce, A.J.; Xue, A.; et al. Identification of Novel Risk Loci, Causal Insights, and Heritable Risk for Parkinson’s Disease: A Meta-Analysis of Genome-Wide Association Studies. Lancet Neurol. 2019, 18, 1091–1102.
  21. Glancy, B.; Kim, Y.; Katti, P.; Willingham, T.B. Focusing on Mitochondrial Form and Function. Nat. Cell Biol. 2018, 20, 735.
  22. Glancy, B.; Kim, Y.; Katti, P.; Willingham, T.B. The Functional Impact of Mitochondrial Structure Across Subcellular Scales. Front. Physiol. 2020, 11, 541040.
  23. Chan, D.C. Mitochondrial Dynamics and Its Involvement in Disease. Annu. Rev. Pathol. Mech. Dis. 2020, 15, 235–259.
  24. Palikaras, K.; Lionaki, E.; Tavernarakis, N. Mechanisms of Mitophagy in Cellular Homeostasis, Physiology and Pathology. Nat. Cell Biol. 2018, 20, 1013–1022.
  25. Lara Ordóñez, A.J.; Fasiczka, R.; Naaldijk, Y.; Hilfiker, S. Rab GTPases in Parkinson’s Disease: A Primer. Essays Biochem. 2021, 65, 961–974.
  26. Müller, M.P.; Goody, R.S. Molecular Control of Rab Activity by GEFs, GAPs and GDI. Small GTPases 2018, 9, 5–21.
  27. Bonet-Ponce, L.; Cookson, M.R. The Role of Rab GTPases in the Pathobiology of Parkinson’ Disease. Curr. Opin. Cell Biol. 2019, 59, 73–80.
  28. Stenmark, H. Rab GTPases as Coordinators of Vesicle Traffic. Nat. Rev. Mol. Cell Biol. 2009, 10, 513–525.
  29. Li, G. Rab GTPases, Membrane Trafficking and Diseases. Curr. Drug Targets 2011, 12, 1188–1193.
  30. D’Adamo, P.; Masetti, M.; Bianchi, V.; Morè, L.; Mignogna, M.L.; Giannandrea, M.; Gatti, S. RAB GTPases and RAB-Interacting Proteins and Their Role in the Control of Cognitive Functions. Neurosci. Biobehav. Rev. 2014, 46, 302–314.
  31. Mignogna, M.L.; D’Adamo, P. Critical Importance of RAB Proteins for Synaptic Function. Small GTPases 2018, 9, 145–157.
  32. Giannandrea, M.; Bianchi, V.; Mignogna, M.L.; Sirri, A.; Carrabino, S.; D’Elia, E.; Vecellio, M.; Russo, S.; Cogliati, F.; Larizza, L.; et al. Mutations in the Small GTPase Gene RAB39B Are Responsible for X-Linked Mental Retardation Associated with Autism, Epilepsy, and Macrocephaly. Am. J. Hum. Genet. 2010, 86, 185–195.
  33. Wilson, G.R.; Sim, J.C.H.; McLean, C.; Giannandrea, M.; Galea, C.A.; Riseley, J.R.; Stephenson, S.E.M.; Fitzpatrick, E.; Haas, S.A.; Pope, K.; et al. Mutations in RAB39B Cause X-Linked Intellectual Disability and Early-Onset Parkinson Disease with α-Synuclein Pathology. Am. J. Hum. Genet. 2014, 95, 729–735.
  34. Niu, M.; Zheng, N.; Wang, Z.; Gao, Y.; Luo, X.; Chen, Z.; Fu, X.; Wang, Y.; Wang, T.; Liu, M.; et al. RAB39B Deficiency Impairs Learning and Memory Partially Through Compromising Autophagy. Front. Cell Dev. Biol. 2020, 8, 598622.
  35. Purlyte, E.; Dhekne, H.S.; Sarhan, A.R.; Gomez, R.; Lis, P.; Wightman, M.; Martinez, T.N.; Tonelli, F.; Pfeffer, S.R.; Alessi, D.R. Rab29 Activation of the Parkinson’s Disease-Associated LRRK2 Kinase. EMBO J. 2018, 37, 1–18.
  36. Steger, M.; Tonelli, F.; Ito, G.; Davies, P.; Trost, M.; Vetter, M.; Wachter, S.; Lorentzen, E.; Duddy, G.; Wilson, S.; et al. Phosphoproteomics Reveals That Parkinson’s Disease Kinase LRRK2 Regulates a Subset of Rab GTPases. eLife 2016, 5, e12813.
  37. Kingwell, K. LRRK2-Targeted Parkinson Disease Drug Advances into Phase III. Nat. Rev. Drug Discov. 2022, 22, 3–5.
  38. Connor-Robson, N.; Booth, H.; Martin, J.G.; Gao, B.; Li, K.; Doig, N.; Vowles, J.; Browne, C.; Klinger, L.; Juhasz, P.; et al. An Integrated Transcriptomics and Proteomics Analysis Reveals Functional Endocytic Dysregulation Caused by Mutations in LRRK2. Neurobiol. Dis. 2019, 127, 512–526.
  39. Zeigerer, A.; Gilleron, J.; Bogorad, R.L.; Marsico, G.; Nonaka, H.; Seifert, S.; Epstein-Barash, H.; Kuchimanchi, S.; Peng, C.G.; Ruda, V.M.; et al. Rab5 Is Necessary for the Biogenesis of the Endolysosomal System in Vivo. Nature 2012, 485, 465–470.
  40. Sung, J.Y.; Kim, J.; Paik, S.R.; Park, J.H.; Ahn, Y.S.; Chung, K.C. Induction of Neuronal Cell Death by Rab5A-Dependent Endocytosis of α-Synuclein. J. Biol. Chem. 2001, 276, 27441–27448.
  41. Dinter, E.; Saridaki, T.; Nippold, M.; Plum, S.; Diederichs, L.; Komnig, D.; Fensky, L.; May, C.; Marcus, K.; Voigt, A.; et al. Rab7 Induces Clearance of α-Synuclein Aggregates. J. Neurochem. 2016, 138, 758–774.
  42. Fang, F.; Yang, W.; Florio, J.B.; Rockenstein, E.; Spencer, B.; Orain, X.M.; Dong, S.X.; Li, H.; Chen, X.; Sung, K.; et al. Synuclein Impairs Trafficking and Signaling of BDNF in a Mouse Model of Parkinson’s Disease. Sci. Rep. 2017, 7, 3868.
  43. Breda, C.; Nugent, M.L.; Estranero, J.G.; Kyriacou, C.P.; Outeiro, T.F.; Steinert, J.R.; Giorgini, F. Rab11 Modulates α-Synuclein-Mediated Defects in Synaptic Transmission and Behaviour. Hum. Mol. Genet. 2015, 24, 1077–1091.
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