Figure 2 - uploaded by José S Ramalho
Content may be subject to copyright.
Rab11a S25N inhibits endosomal recycling in aSyn expressing cells. (A) aSyn WT expressing SH-SY5Y cells were transfected with mock (EGFP), EGFP-Rab11a WT or EGFP-Rab11a S25N expressing plasmids (green). Twenty-four hours post-transfection, cells were incubated with Alexa-546 human transferrin (red) for 15 min and pulse-chased with non-labeled human transferrin to measure endocytic recycling dynamics. Cells were fixed and subjected to fluorescence microscopy analysis. Scale bar ¼ 10 mm. (B) Data are represented as percentage of Alexa-546-transferrin-positive cells at 10 min pulse-chase. All the data shown are representative of at least three independent experiments (mean + SD, * * P , 0.01).
Source publication
Alpha-synuclein (aSyn) misfolding and aggregation are pathological features common to several neurodegenerative diseases,
including Parkinson's disease (PD). Mounting evidence suggests that aSyn can be secreted and transferred from cell to cell,
participating in the propagation and spreading of pathological events. Rab11, a small GTPase, is an impo...
Contexts in source publication
Context 1
... on the cell surface and is recovered to the extracellular milieu by endocytic recycling (45). Twenty-four hours post- transfection with EGFP-Rab11a WT, EGFP-Rab11a S25N or EGFP alone, aSyn expressing SH-SY5Y cells were loaded for 15 min with Alexa-546-labeled human transferrin and pulse- chased for 10 min with non-labeled human transferrin ( Fig. 2A). We evaluated the percentage of Alexa-546-transferrin positive cells in each condition by fluorescence microscopy, as a measure of endosomal recycling dynamics. Compared with control transfected cells, there was no significant difference in the percentage of fluorescently labeled transferrin cells in the case of EGFP-Rab11a WT ...
Context 2
... Fig. 2A). We evaluated the percentage of Alexa-546-transferrin positive cells in each condition by fluorescence microscopy, as a measure of endosomal recycling dynamics. Compared with control transfected cells, there was no significant difference in the percentage of fluorescently labeled transferrin cells in the case of EGFP-Rab11a WT expression (Fig. 2B). In contrast, we observed a significantly higher proportion of Alexa- 546-transferrin-labelled cells expressing EGFP-Rab11a S25N when compared with EGFP expressing cells (Fig. 2B). These results indicate that endocytic recycling is impaired in the pres- ence of the dominant negative, GDP-bound Rab11a mutant, as less transferrin was ...
Context 3
... control transfected cells, there was no significant difference in the percentage of fluorescently labeled transferrin cells in the case of EGFP-Rab11a WT expression (Fig. 2B). In contrast, we observed a significantly higher proportion of Alexa- 546-transferrin-labelled cells expressing EGFP-Rab11a S25N when compared with EGFP expressing cells (Fig. 2B). These results indicate that endocytic recycling is impaired in the pres- ence of the dominant negative, GDP-bound Rab11a mutant, as less transferrin was secreted from the cells, while the expression of Rab11a WT did not affect endocytic recycling. Therefore, we conclude that increased secretion of aSyn from SH-SY5Y cells mediated by ...
Context 4
... investigate whether the increased secretion of aSyn observed upon co-expression of Rab11a WT or Rab11a S25N occurred through changes in endocytic recycling, we measured endocytic recycling dynamics using fluorescently labeled human transfer- rin. Transferrin is internalized by endocytosis after binding to its receptor on the cell surface and is recovered to the extracellular milieu by endocytic recycling (45). Twenty-four hours post- transfection with EGFP-Rab11a WT, EGFP-Rab11a S25N or EGFP alone, aSyn expressing SH-SY5Y cells were loaded for 15 min with Alexa-546-labeled human transferrin and pulse- chased for 10 min with non-labeled human transferrin ( Fig. 2A). We evaluated the percentage of Alexa-546-transferrin positive cells in each condition by fluorescence microscopy, as a measure of endosomal recycling dynamics. Compared with control transfected cells, there was no significant difference in the percentage of fluorescently labeled transferrin cells in the case of EGFP-Rab11a WT expression (Fig. 2B). In contrast, we observed a significantly higher proportion of Alexa- 546-transferrin-labelled cells expressing EGFP-Rab11a S25N when compared with EGFP expressing cells (Fig. 2B). These results indicate that endocytic recycling is impaired in the pres- ence of the dominant negative, GDP-bound Rab11a mutant, as less transferrin was secreted from the cells, while the expression of Rab11a WT did not affect endocytic recycling. Therefore, we conclude that increased secretion of aSyn from SH-SY5Y cells mediated by Rab11a is not due to increased trafficking of aSyn via the endosomal recycling ...
Context 5
... investigate whether the increased secretion of aSyn observed upon co-expression of Rab11a WT or Rab11a S25N occurred through changes in endocytic recycling, we measured endocytic recycling dynamics using fluorescently labeled human transfer- rin. Transferrin is internalized by endocytosis after binding to its receptor on the cell surface and is recovered to the extracellular milieu by endocytic recycling (45). Twenty-four hours post- transfection with EGFP-Rab11a WT, EGFP-Rab11a S25N or EGFP alone, aSyn expressing SH-SY5Y cells were loaded for 15 min with Alexa-546-labeled human transferrin and pulse- chased for 10 min with non-labeled human transferrin ( Fig. 2A). We evaluated the percentage of Alexa-546-transferrin positive cells in each condition by fluorescence microscopy, as a measure of endosomal recycling dynamics. Compared with control transfected cells, there was no significant difference in the percentage of fluorescently labeled transferrin cells in the case of EGFP-Rab11a WT expression (Fig. 2B). In contrast, we observed a significantly higher proportion of Alexa- 546-transferrin-labelled cells expressing EGFP-Rab11a S25N when compared with EGFP expressing cells (Fig. 2B). These results indicate that endocytic recycling is impaired in the pres- ence of the dominant negative, GDP-bound Rab11a mutant, as less transferrin was secreted from the cells, while the expression of Rab11a WT did not affect endocytic recycling. Therefore, we conclude that increased secretion of aSyn from SH-SY5Y cells mediated by Rab11a is not due to increased trafficking of aSyn via the endosomal recycling ...
Context 6
... investigate whether the increased secretion of aSyn observed upon co-expression of Rab11a WT or Rab11a S25N occurred through changes in endocytic recycling, we measured endocytic recycling dynamics using fluorescently labeled human transfer- rin. Transferrin is internalized by endocytosis after binding to its receptor on the cell surface and is recovered to the extracellular milieu by endocytic recycling (45). Twenty-four hours post- transfection with EGFP-Rab11a WT, EGFP-Rab11a S25N or EGFP alone, aSyn expressing SH-SY5Y cells were loaded for 15 min with Alexa-546-labeled human transferrin and pulse- chased for 10 min with non-labeled human transferrin ( Fig. 2A). We evaluated the percentage of Alexa-546-transferrin positive cells in each condition by fluorescence microscopy, as a measure of endosomal recycling dynamics. Compared with control transfected cells, there was no significant difference in the percentage of fluorescently labeled transferrin cells in the case of EGFP-Rab11a WT expression (Fig. 2B). In contrast, we observed a significantly higher proportion of Alexa- 546-transferrin-labelled cells expressing EGFP-Rab11a S25N when compared with EGFP expressing cells (Fig. 2B). These results indicate that endocytic recycling is impaired in the pres- ence of the dominant negative, GDP-bound Rab11a mutant, as less transferrin was secreted from the cells, while the expression of Rab11a WT did not affect endocytic recycling. Therefore, we conclude that increased secretion of aSyn from SH-SY5Y cells mediated by Rab11a is not due to increased trafficking of aSyn via the endosomal recycling ...
Similar publications
Alpha-synuclein (α-syn) is a small protein that, in neurons, localizes predominantly to presynaptic terminals. Due to elevated conformational plasticity, which can be affected by environmental factors, in addition to undergoing disorder-to-order transition upon interaction with different interactants, α-syn is counted among the intrinsically disord...
Background: Given the overlap of clinical manifestations and pathological characteristics between Parkinson's disease (PD) and multiple system atrophy (MSA), we investigated the associations between five functional polymorphisms of nucleotide-binding oligomerization domain protein 2 (NOD2) which were associated with PD, and MSA in a Chinese populat...
Background
Alpha-synuclein (α-syn) aggregation represents the pathological hallmark of α-synucleinopathies like Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Toll-like receptors (TLRs) are a family of highly conserved molecules that recognize pathogen-associated molecular patterns and define the innat...
Citations
... In this regard, most in vitro studies focus on DA neurons alone and under non-physiological adherent conditions (i.e. 2D monolayers), ignoring microenvironmental factors that influence disease progression [12][13][14][15][16]. Animal disease models, despite presenting the most comparable pathologies to PD in humans [17], are highly limited by their low throughput, as well as by species-specific physiological differences. ...
Parkinson’s disease (PD) is a complex and multifaceted neurodegenerative disorder that results from multiple environmental factors and multicellular interactions. Although several PD neuropathologies have been identified and described, the thorough understanding of PD pathophysiology and research has been largely limited by the absence of reliable in vitro models that truly recapitulate PD microenvironments. Here, we propose a neuroimmune co-culture system that models PD neuropathologies by combining relevant multicellular interactions with environments that mimic the brain. This system is composed of: (i) 3D bioprinted cultures of mature human dopaminergic neurons grown on extracellular matrix (ECM)-derived scaffolds doped with electroconductive nanostructures, and (ii) a direct co-culture of human astrocytes and differentiated monocytes that models neuroinflammatory responses. When co-cultured in a transwell format, these two compartments recreate relevant multicellular environments that model Parkinson's disease pathologies after exposure to the neurotoxin A53T α-synuclein. With immunofluorescent staining and gene expression analyses, we show that functional and mature dopaminergic 3D networks are generated within our ECM-derived scaffolds with superior performance to standard 2D cultures. Moreover, by analyzing cytokine secretion, cell surface markers, and gene expression, we define a human monocyte differentiation scheme that allows the appearance of both monocyte-derived macrophages and dendritic cell phenotypes, as well as their optimal co-culture ratios with human astrocytes to recreate synergistic neuroinflammatory responses. We show that the combined response of both compartments to A53T α−synuclein stimulates the formation of intracellular α-synuclein aggregates, induces progressive mitochondrial dysfunction and ROS production, downregulates the expression of synaptic, dopaminergic, and mitophagy-related genes, and promotes the initiation of apoptotic processes within the dopaminergic networks. Most importantly, these intracellular pathologies were comparable or superior to those generated with a rotenone-stimulated 2D control that represents the current standard for in vitro PD models and showed increased resilience towards these neurotoxic insults, allowing the study of disease progression over longer time periods than current models.
... Rab GTP enzymes such as Rab11, Rab35, Rab27a, and Rab27b participate in the production of exosomes through vesicle budding [64][65][66]. The expression of exosomal markers such as CD63 was shown to be reduced by the silencing of Rab27a and Rab27b [67,68]. ...
Induced pluripotent stem cell (iPSC) therapy brings great hope to the treatment of myocardial injuries, while extracellular vesicles may be one of the main mechanisms of its action. iPSC-derived small extracellular vesicles (iPSCs-sEVs) can carry genetic and proteinaceous substances and mediate the interaction between iPSCs and target cells. In recent years, more and more studies have focused on the therapeutic effect of iPSCs-sEVs in myocardial injury. IPSCs-sEVs may be a new cell-free-based treatment for myocardial injury, including myocardial infarction, myocardial ischemia–reperfusion injury, coronary heart disease, and heart failure. In the current research on myocardial injury, the extraction of sEVs from mesenchymal stem cells induced by iPSCs was widely used. Isolation methods of iPSCs-sEVs for the treatment of myocardial injury include ultracentrifugation, isodensity gradient centrifugation, and size exclusion chromatography. Tail vein injection and intraductal administration are the most widely used routes of iPSCs-sEV administration. The characteristics of sEVs derived from iPSCs which were induced from different species and organs, including fibroblasts and bone marrow, were further compared. In addition, the beneficial genes of iPSC can be regulated through CRISPR/Cas9 to change the composition of sEVs and improve the abundance and expression diversity of them. This review focused on the strategies and mechanisms of iPSCs-sEVs in the treatment of myocardial injury, which provides a reference for future research and the application of iPSCs-sEVs.
... This has been the case for neurological disorders such as Parkinson's or Alzheimer disease where the modulation of the endocytic pathway through Rab11 expression affected asynuclein aggregation and b-amiloid production 80,81 . Similarly, several reports have associated Rab14 to cancer development which could be affected by the inhibition of the Rab4-Rab14-Rab11 cascade 26,32,82,83 While the molecular details of the Rab14, and as a consequence PARP12, activity in the pathogenesis of these diverse diseases have yet to be defined, their mechanistic role in these processes arises the interest in them as druggable enzyme/s amenable to pharmacological development toward therapies. ...
The GTPase Rab14 is localized at the trans-Golgi network and at the intermediate compartment associated to sorting/recycling endosomes-like structures of the transferrin-recycling pathway: as other Rab family members, it is involved in the regulation of intracellular vesicle trafficking, though its role and functional relationship with effector/endosomal proteins is still incomplete.
We have analysed whether post-translational modifications could affect Rab14 activity: the results obtained define mono-ADP-ribosylation (MARylation) as the yet-unknown Rab14 modification, catalysed by the ADP-ribosyltransferase PARP12, which specifically modifies glutamic acid residues in position 159/162. This modification is essential for the Rab14-dependent endosome progression. Accordingly, recycling of the transferrin receptor is inhibited when MARylation of Rab14 is prevented by PARP12 knocking-down or inhibition, or by overexpression of Rab14 ADP-ribosylation-defective mutant. Under these conditions, Rab14 and transferrin receptors are withheld at the cell periphery at the level of the Rab4-RUFY1-positive sorting endosomes, indicating that the interaction of Rab14 with the dual effectors RUFY and then FIP1c (which specifically binds both Rab11 and Rab14) determines the progression between the Rab4-RUFY- and Rab11-FIP1c-specific vesicles. Therefore Rab14-MARylation determines the sequential binding of this GTPase to RUFY and FIP1c, thus controlling endosome progression ( i . e ., transferrin receptors recycling) through the Rab4-, Rab14- and Rab11-specific vesicles. This identifies a Rab14-specific compartment of the recycling pathway and a crucial enzymatic reaction amenable to pharmacological control.
... RAB11 was found to be downregulated in all the ALS samples while phosphor-AKT and phosphor-S6 kinase were upregulated (Mitra et al. 2019). Loss of RAB11 is associated with ALS and overexpression of RAB11 was found to be neuroprotective (Chutna et al. 2014). However, in the mice model of ALS carboxy-terminal modulator protein which regulates AKT signaling by reducing the activity of AKT was found to be upregulated. ...
Amyotrophic lateral Sclerosis is an incurable, progressive neurodegenerative motor neuron disease. The disease is characterized by protein aggregates. The symptoms include weakness, denervation of muscles, atrophy and progressive paralysis of bulbar and respiratory muscles and dysphagia. Various secondary metabolites are evaluated for their ability to improve symptoms in ALS. Ginseng has been traditionally used for treating several neurodegenerative diseases. Several studies using model systems have shown a potential role of Ginseng catechins and Ginsenosides in clearing protein aggregation associated with ALS. We focus on Network pharmacology approach to understand the effect of Ginseng catechins or ginsenosides on protein aggregation associated with ALS. A catechin/ginsenoside-protein interaction network was generated and the pathways obtained were compared with those obtained from transcriptomic datasets of ALS from GEO database. Knock out of MAPK14, AKT and GSK from Catechin and BACE 1 from ginsenoside modulated pathways inhibited protein aggregation. Catechins and ginsenosides have potential as therapeutic agents in the management of ALS.
Supplementary information:
The online version contains supplementary material available at 10.1007/s13205-022-03401-1.
... While the research is still limited, there has been evidence that the overexpression of certain Rab proteins can curb pathogenic α-synuclein toxicity [81]. Experimental evidence has indicated that proteins Rab3A [72], Rab8b, Rab11a, and Rab13 [82] promote the clearance of α-synuclein aggregates, thereby preventing α-synuclein-induced toxicity. Additionally, α-synuclein monomers and oligomers cooperatively inhibit neuronal SNARE-mediated vesicle fusion and at sub-micromolar concentrations, α-synuclein monomers increased the fusion inhibition by α-synuclein oligomers [83]. ...
α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson’s disease. Aggregated α-synuclein can impair both synaptic functioning and axonal transport. However, understanding the pathological role that α-synuclein plays at a cellular level is complicated as existing findings are multifaceted and dependent on the mutation, the species, and the quantity of the protein that is involved. This systematic review aims to stratify the research findings to develop a more comprehensive understanding of the role of aggregated α-synuclein on synaptic and axonal proteins in Parkinson’s disease models. A literature search of the PubMed, Scopus, and Web of Science databases was conducted and a total of 39 studies were included for analysis. The review provides evidence for the dysregulation or redistribution of synaptic and axonal proteins due to α-synuclein toxicity. However, due to the high quantity of variables that were used in the research investigations, it was challenging to ascertain exactly what effect α-synuclein has on the expression of the proteins. A more standardized experimental approach regarding the variables that are employed in future studies is crucial so that existing literature can be consolidated. New research involving aggregated α-synuclein at the synapse and regarding axonal transport could be advantageous in guiding new treatment solutions.
... More recent work has extended this focus to the area of SV cluster organization and the potential roles of a-Syn as a modulator of liquid-liquid phase separation processes at presynaptic nerve terminals (12,61). Studies of pathways influenced by a-Syn in living cells have highlighted both functional and pathological interactions between a-Syn and Rab proteins (8,27,33,(62)(63)(64)(65), which act as master regulators of vesicle trafficking pathways in eukaryotic cells (66). Functional interactions of a-Syn specifically with Rab3a, the primary Rab regulating SV trafficking (67), have also been reported (27,33,34,68). ...
Alpha-synuclein (a-Syn) is a presynaptic protein, the misfolding of which is associated with Parkinson's disease (PD). Rab GTPases are small guanine nucleotide binding proteins that play key roles in vesicle trafficking and have been associated with a-Syn function and dysfunction. A-Syn is enriched on synaptic vesicles (SVs), where it has been reported to interact with GTP-bound Rab3a, a master regulator of SV trafficking. A-Syn is known to bind weakly to Rab8a in solution via a positively charged patch, but the physiological implications of such interactions have not been explored. Here, we investigate direct interactions between a-Syn and Rab3a in solution and on lipid membranes using NMR spectroscopy. We find that the C-terminus of a-Syn interacts with Rab3a in a manner similar to its previously reported interaction with Rab8a. While weak in solution, we demonstrate that this interaction becomes stronger when the proteins are bound to a membrane surface. The Rab3a binding site for a-Syn is similar to the surface that contacts the Rab3a effector rabphilin-3A, which modulates the enzymatic activity of Rab3a. Accordingly, we show that a-Syn inhibits GTP hydrolysis by Rab3a, and that inhibition is more potent on the membrane surface, suggesting that their interaction may be functionally relevant. Finally, we show that phosphorylation of a-Syn residue Ser-129, a modification associated with PD pathology, enhances its interactions with Rab3a and increases its ability to inhibit Rab3a GTP hydrolysis. These results represent the first observation of a functional role for synuclein-Rab interactions and for a-Syn Ser-129 phosphorylation.
... In mouse models, aSyn has been shown to interact with several Rabs, impairing intracellular transport (Dalfó et al., 2004). Between them, Rab11 interacts with aSyn and is present in intracellular inclusions together with aSyn (Chutna et al., 2014). aSyn has been detected to colocalize with endosomal compartments positive for Rab5, Rab7, and Rab11, in which a portion of endogenous aSyn is trafficked through Rab11 endosomes (Liu et al., 2009). ...
... aSyn has been detected to colocalize with endosomal compartments positive for Rab5, Rab7, and Rab11, in which a portion of endogenous aSyn is trafficked through Rab11 endosomes (Liu et al., 2009). In pathological models, Rab11 is involved in the regulation of aSyn secretion, reducing the cytotoxicity of aSyn (Chutna et al., 2014). In Drosophila models of PD, aSyn increased synaptic vesicles, inducing impairment in locomotion, inducing cell death of dopaminergic neurons, and shortening the lifespan. ...
Neurons are highly polarized cells that rely on the intracellular transport of organelles. This process is regulated by molecular motors such as dynein and kinesins and the Rab family of monomeric GTPases that together help move cargo along microtubules in dendrites, somas, and axons. Rab5-Rab11 GTPases regulate receptor trafficking along early-recycling endosomes, which is a process that determines the intracellular signaling output of different signaling pathways, including those triggered by BDNF binding to its tyrosine kinase receptor TrkB. BDNF is a well-recognized neurotrophic factor that regulates experience-dependent plasticity in different circuits in the brain. The internalization of the BDNF/TrkB complex results in signaling endosomes that allow local signaling in dendrites and presynaptic terminals, nuclear signaling in somas and dynein-mediated long-distance signaling from axons to cell bodies. In this review, we briefly discuss the organization of the endocytic pathway and how Rab11-recycling endosomes interact with other endomembrane systems. We further expand upon the roles of the Rab11-recycling pathway in neuronal plasticity. Then, we discuss the BDNF/TrkB signaling pathways and their functional relationships with the postendocytic trafficking of BDNF, including axonal transport, emphasizing the role of BDNF signaling endosomes, particularly Rab5-Rab11 endosomes, in neuronal plasticity. Finally, we discuss the evidence indicating that the dysfunction of the early-recycling pathway impairs BDNF signaling, contributing to several neurodegenerative diseases.
... Parkinson's disease is the second most common neurodegenerative disorder associated with aging and is characterized by the loss of dopaminergic neurons and the formation of aggregations of alphasynuclein protein (aSyn) called Lewy bodies. Rab11A interacts with aSyn and modulates its aggregation and clearance (Chutna et al., 2014;Gonçalves et al., 2016). ...
The coordinated actions of the endosomal uptake and recycling pathways are one of the main cellular mechanisms for controlling the composition of the plasma membrane. Once endocytosed from the cell surface, proteins and membrane lipids typically undergo one of two fates. They can either be sent along the degradative pathway to lysosomes where they are broken down, or they are returned to the plasma membrane by the endosomal recycling pathway. Molecules that are recycled to the plasma membrane must undergo a complex series of sorting events, that occur in several organelles, prior to reaching their destination. Members of the Rab family of small GTPases are key regulators of this process.
... The number of additional potential aSyn-binding proteins may truthfully be said to be overwhelming. Monomeric and oligomeric forms of aSyn may bind to small GTPases for internalization and sorting in cells 145,146 and over 100 synaptosome components, including synapsin I, VAMP-2 and hundreds of additional synaptic proteins 147,148 . Wild-type aSyn binds to tubulin and microtubules and may enable appropriate aSyn folding, a function that could be absent in disease-causing mutants 149 . ...
With the advent of the genetic era in Parkinson’s disease (PD) research in 1997, α-synuclein was identified as an important player in a complex neurodegenerative disease that affects >10 million people worldwide. PD has been estimated to have an economic impact of $51.9 billion in the US alone. Since the initial association with PD, hundreds of researchers have contributed to elucidating the functions of α-synuclein in normal and pathological states, and these remain critical areas for continued research. With this position paper the authors strive to achieve two goals: first, to succinctly summarize the critical features that define α-synuclein’s varied roles, as they are known today; and second, to identify the most pressing knowledge gaps and delineate a multipronged strategy for future research with the goal of enabling therapies to stop or slow disease progression in PD.
... Moreover, yeast putative transmembrane protein 1 (Ytp1), the Rab protein ortholog in yeast, has been shown to predominantly colocalize with α-syn inclusions [17]. Additionally, certain Rab proteins, namely Rab3a, Rab8, and Rab11a, are able to directly interact with α-syn in cell culture and in vivo, reducing α-syn-induced toxicity [72][73][74][75]. ...
Abnormal accumulation of the protein α- synuclein (α-syn) into proteinaceous inclusions called Lewy bodies (LB) is the neuropathological hallmark of Parkinson’s disease (PD) and related disorders. Interestingly, a growing body of evidence suggests that LB are also composed of other cellular components such as cellular membrane fragments and vesicular structures, suggesting that dysfunction of the endolysosomal system might also play a role in LB formation and neuronal degeneration. Yet the link between α-syn aggregation and the endolysosomal system disruption is not fully elucidated. In this review, we discuss the potential interaction between α-syn and the endolysosomal system and its impact on PD pathogenesis. We propose that the accumulation of monomeric and aggregated α-syn disrupt vesicles trafficking, docking, and recycling, leading to the impairment of the endolysosomal system, notably the autophagy-lysosomal degradation pathway. Reciprocally, PD-linked mutations in key endosomal/lysosomal machinery genes (LRRK2, GBA, ATP13A2) also contribute to increasing α-syn aggregation and LB formation. Altogether, these observations suggest a potential synergistic role of α-syn and the endolysosomal system in PD pathogenesis and represent a viable target for the development of disease-modifying treatment for PD and related disorders.
