In Situ Peroxidase Labeling and Mass-Spectrometry Connects Alpha-Synuclein Directly to Endocytic Trafficking and mRNA Metabolism in Neurons

Chung, Chee Yeun; Khurana, Vikram; Yi, S. Stephen; Sahni, Nidhi; Loh, Ken H.; Auluck, Pavan K.; Baru, Valeriya; Udeshi, Namrata D.; Freyzon, Yelena; Carr, Steven A.; Hill, David E.; Vidal, Marc; Ting, Alice Y.; Lindquist, Susan

doi:10.1016/j.cels.2017.01.002

Cited by 94 publications

(108 citation statements)

References 46 publications

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“…In addition to the many terms related to fatty acid metabolism, gene ontology analysis also revealed other enriched terms, including myofibril assembly, muscle α‐actinin binding, and sperm flagellum. The component transcripts responsible for these terms being enriched are cytoskeletal genes (Figure b, Table ), which is of interest given our work (Ordonez et al, ) as well as the work of others (Chung et al, ; Esposito, Dohm, Kermer, Bähr, & Wouters, ; Khurana et al, ; Sousa et al, ) implicating dysfunction of the actin cytoskeleton in α‐synuclein neurotoxicity. Similar to the fatty acid metabolism‐related genes, the cytoskeletal genes were also downregulated in Neuron:Control (Figure b), though none reached statistical significance in that condition.…”

Section: Resultsmentioning

confidence: 56%

Glial α‐synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

Olsen

Feany

2019

Glia

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α‐Synucleinopathies are neurodegenerative diseases that are characterized pathologically by α‐synuclein inclusions in neurons and glia. The pathologic contribution of glial α‐synuclein in these diseases is not well understood. Glial α‐synuclein may be of particular importance in multiple system atrophy (MSA), which is defined pathologically by glial cytoplasmic α‐synuclein inclusions. We have previously described Drosophila models of neuronal α‐synucleinopathy, which recapitulate key features of the human disorders. We have now expanded our model to express human α‐synuclein in glia. We demonstrate that expression of α‐synuclein in glia alone results in α‐synuclein aggregation, death of dopaminergic neurons, impaired locomotor function, and autonomic dysfunction. Furthermore, co‐expression of α‐synuclein in both neurons and glia worsens these phenotypes as compared to expression of α‐synuclein in neurons alone. We identify unique transcriptomic signatures induced by glial as opposed to neuronal α‐synuclein. These results suggest that glial α‐synuclein may contribute to the burden of pathology in the α‐synucleinopathies through a cell type‐specific transcriptional program. This new Drosophila model system enables further mechanistic studies dissecting the contribution of glial and neuronal α‐synuclein in vivo, potentially shedding light on mechanisms of disease that are especially relevant in MSA but also the α‐synucleinopathies more broadly.

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Section: Resultsmentioning

confidence: 56%

Glial α‐synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

Olsen

Feany

2019

Glia

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“…These proteins have been shown to play a part in various neurodegenerative diseases through their role in cellular functions including but not limited to endocytosis, vesicle trafficking, vesicle docking, ciliogenesis and interactions in the trans-Golgi network (Schimmöller et al, 1998;Rodman and Wandinger-Ness, 2000;Seabra et al, 2002). While the Rab family encompasses roughly 50 proteins with variable functions across the vesicular pathway, 10 have been shown to have a possible relationship to PD either directly or indirectly (Gonçalves et al, 2016;Steger et al, 2016;Chung et al, 2017). The myriad of functions attributed to the Rab proteins and the varied hypothesized routs to pathogenesis in PD can be summarized as the following three pathways: endocytic function and lysosomal stress, ciliogenesis and sonic hedgehog signaling and, lastly the trans-Golgi network and endoplasmic reticulum (ER) stress.…”

Section: Rab Proteinsmentioning

confidence: 99%

“…A number of Rab proteins (RAb8b, Rab11a, and Rab13) have impact on α-synuclein clearance which can have consequences on α-synuclein aggregation (Gonçalves et al, 2016). Similarly, Rab8A has also been shown to play a role in membrane trafficking and clearance as well as protein transport (Chung et al, 2017). Further evidence for the role of Rab8A in development and pathogenesis comes as studies have shown that LRRK2 phosphorylation of Rab8A can cause centrosomal defects and thus cause widespread effects on neurite growth and migration (Madero-Pérez et al, 2018a).…”

Section: Rab Proteinsmentioning

confidence: 99%

Vesicular Dysfunction and the Pathogenesis of Parkinson’s Disease: Clues From Genetic Studies

Ebanks

Lewis

2020

Front. Neurosci.

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Parkinson's disease (PD) is a common age-related neurodegenerative disorder with disabling motor symptoms and no available disease modifying treatment. The majority of the PD cases are of unknown etiology, with both genetics and environment playing important roles. Over the past 25 years, however, genetic analysis of patients with familial history of Parkinson's and, latterly, genome wide association studies (GWAS) have provided significant advances in our understanding of the causes of the disease. These genetic insights have uncovered pathways that are affected in both genetic and sporadic forms of PD. These pathways involve oxidative stress, abnormal protein homeostasis, mitochondrial dysfunction, and lysosomal defects. In addition, newly identified PD genes and GWAS nominated genes point toward synaptic changes involving vesicles. This review will highlight the genes that contribute PD risk relating to intracellular vesicle trafficking and their functional consequences. There is still much to investigate on this newly identified and converging pathway of vesicular dynamics and PD, which will aid in better understanding and suggest novel therapeutic strategies for PD patients.

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“…The connection between retromer and a-synuclein is further supported by evidence from recent proteomic studies [109]. By using the ascorbate peroxidase (APEX)-labelling biotinylation combined with mass spectrometry, a-synuclein has been shown to directly interact with Vps29 as well as SNX1 [110]. Overall, these findings collectively suggest that retromer may modulate a-synuclein trafficking and biogenesis either in an indirect manner with cathepsin D, or in a direct manner by direct interaction.…”

Section: Connectivity Of Retromer With Other Pdassociated Proteinsmentioning

confidence: 75%

The functional roles of retromer in Parkinson's disease

2017

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The endosomal system is critical for the maintenance of intracellular homeostasis, and defects in this system are often linked to neurological disorders. The retromer complex is a critical coordinator of endosomal dynamics and has functional roles in multiple cellular processes through sorting cargoes from endosomes to the trans-Golgi network (TGN) or to the plasma membrane. Mammalian retromer comprises a core Vps26-Vps35-Vps29 trimer and associates with a range of proteins to generate endosomal tubular-vesicular carriers. Alterations in retromer function or its molecular organization have been a rising risk factor for Parkinson's disease (PD). Although genetic evidence has shown several variants within retromer in late-onset PD cases, the exact molecular machineries by which retromer variants induce the development of PD are still not completely elucidated. In this Review, we will focus on the functional roles of retromer in neuronal health, summarize advances in defining the cellular pathological phenotype caused by retromer deficiency or PD-linked retromer variants and discuss the potential clues of how retromer deregulation may contribute to PD pathogenesis.Keywords: autophagy; endosomal trafficking; lysosome; mitochondria; Parkinson's disease (PD); retromer The endosomal network is a highly dynamic and orchestrated system, which serves a vital function in coordinating the communication and exchange of associated proteins and lipids between intracellular membrane-bounded compartments. Once within the network, cargo molecules originating from the plasma membrane and biosynthetic pathways are targeted to a common sorting station, the early endosome, from where cargoes are sorted towards specialized intracellular locations following multiple trafficking routes. They can be either sorted into late endosomes/ lysosomes for degradation or retrieved to the plasma membrane or the trans-Golgi network (TGN). The efficient and accurate delivery of cargo contents within intracellular compartments is critical for the maintenance of intracellular homeostasis, and defects on it are often associated with multiple human diseases. The evolutionary conserved protein complex, termed Abbreviations AMPAR, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; APEX, ascorbate peroxidase; APP, b-amyloid precursor protein; ATG9A, autophagy-associated protein; Ab, elevated b-amyloid peptide; BAR, Bin-Amphiphysin-Rvs; BDNF, brain-derived neurotrophic factor; CI-M6PR, cation-independent mannose 6-phosphate receptor; CLN5, ceroid lipouscinosis neuronal protein-5; CMA, chaperon-mediated autophagy; Crb, crumb; DA, dopaminergic; DMTI-II, divalent metal transporter II; DRD1, dopamine receptor D1; Drp1, dynamin-related protein 1; EHD1, Eps15 homology domain-containing protein-1; FERM, 4.1/ezrin/radixin/moesin; GLUT1, glucose transporter 1; Kir3, G protein-gated inward rectifying potassium channels; Lamp2a, lysosome-associated membrane glycoprotein 2a; LBs, Lewy bodies; MAPL, mitochondria-anchored protein ligase; MDVs, mitochondria-de...

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In Situ Peroxidase Labeling and Mass-Spectrometry Connects Alpha-Synuclein Directly to Endocytic Trafficking and mRNA Metabolism in Neurons

Cited by 94 publications

References 46 publications

Glial α‐synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

Glial α‐synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

Vesicular Dysfunction and the Pathogenesis of Parkinson’s Disease: Clues From Genetic Studies

The functional roles of retromer in Parkinson's disease

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