scholarly journals The Parkinson’s Disease Protein LRRK2 Interacts with the GARP Complex to Promote Retrograde Transport to the trans-Golgi Network

Cell Reports ◽  
2020 ◽  
Vol 31 (5) ◽  
pp. 107614 ◽  
Author(s):  
Alexandra Beilina ◽  
Luis Bonet-Ponce ◽  
Ravindran Kumaran ◽  
Jennifer J. Kordich ◽  
Morié Ishida ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Retrograde Transport ◽  
Trans Golgi Network ◽  
Disease Protein ◽  
Golgi Network ◽  
Garp Complex

scholarly journals Altered striatal dopamine levels in Parkinson’s disease VPS35 D620N mutant transgenic aged mice

2020 ◽  
Author(s):  
Sarivin Vanan ◽  
Xiaoxia Zeng ◽  
Sook Yoong Chia ◽  
Katarina Varnäs ◽  
Mei Jiang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Retrograde Transport ◽  
Striatal Dopamine ◽  
Dopamine Level ◽  
Expression Platform ◽  
Cargo Proteins ◽  
Vacuolar Protein ◽  
Golgi Network ◽  
Old Mice

Abstract Vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex that mediates the retrograde transport of cargo proteins from endosomes to the trans-Golgi network. Mutations such as D620N in the VPS35 gene have been identified in patients with autosomal dominant Parkinson’s disease (PD). However, it remains poorly understood whether and how VPS35 deficiency or mutation contributes to PD pathogenesis; specifically, the studies that have examined VPS35 thus far have differed in results and methodologies. We generated a VPS35 D620N mouse model using a Rosa26-based transgene expression platform to allow expression in a spatial manner, so as to better address these discrepancies. Here, aged (20-months-old) mice were first subjected to behavioral tests. Subsequently, DAB staining analysis of substantia nigra (SN) dopaminergic neurons with the marker for tyrosine hydroxylase (TH) was performed. Next, HPLC was used to determine dopamine levels, along with levels of its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum. Western blotting was also performed to study the levels of key proteins associated with PD. Lastly, autoradiography (ARG) evaluation of [3H]FE-PE2I binding to the striatal dopamine transporter DAT was carried out. We found that VPS35 D620N Tg mice displayed a significantly higher dopamine level than NTg counterparts. All results were then compared with that of current VPS35 studies to shed light on the disease pathogenesis. Our model allows future studies to explicitly control spatial expression of the transgene which would generate a more reliable PD phenotype.

scholarly journals Action of Arl1 GTPase and golgin Imh1 in Ypt6-independent retrograde transport from endosomes to the trans-Golgi network

2019 ◽  
Vol 30 (8) ◽  
pp. 1008-1019 ◽  
Author(s):  
Yan-Ting Chen ◽  
I-Hao Wang ◽  
Yi-Hsun Wang ◽  
Wan-Yun Chiu ◽  
Jen-Hao Hu ◽  
...  
Keyword(s):  
Membrane Traffic ◽  
Retrograde Transport ◽  
Vesicle Formation ◽  
Ample Evidence ◽  
Trans Golgi Network ◽  
Growth Defects ◽  
Trafficking Defects ◽  
Golgi Network ◽  
Lipid Flippase ◽  
Garp Complex

The Arf and Rab/Ypt GTPases coordinately regulate membrane traffic and organelle structure by regulating vesicle formation and fusion. Ample evidence has indicated that proteins in these two families may function in parallel or complementarily; however, the manner in which Arf and Rab/Ypt proteins perform interchangeable functions remains unclear. In this study, we report that a Golgi-localized Arf, Arl1, could suppress Ypt6 dysfunction via its effector golgin, Imh1, but not via the lipid flippase Drs2. Ypt6 is critical for the retrograde transport of vesicles from endosomes to the trans-Golgi network (TGN), and its mutation leads to severe protein mislocalization and growth defects. We first overexpress the components of the Arl3-Syt1-Arl1-Imh1 cascade and show that only Arl1 and Imh1 can restore endosome-to-TGN trafficking in ypt6-deleted cells. Interestingly, increased abundance of Arl1 or Imh1 restores localization of the tethering factor Golgi associated retrograde–protein (GARP) complex to the TGN in the absence of Ypt6. We further show that the N-terminal domain of Imh1 is critical for restoring GARP localization and endosome-to-TGN transport in ypt6-deleted cells. Together, our results reveal the mechanism by which Arl1-Imh1 facilitates the recruitment of GARP to the TGN and compensates for the endosome-to-TGN trafficking defects in dysfunctional Ypt6 conditions.

scholarly journals Altered striatal dopamine levels in Parkinson’s disease VPS35 D620N mutant transgenic aged mice

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Sarivin Vanan ◽  
Xiaoxia Zeng ◽  
Sook Yoong Chia ◽  
Katarina Varnäs ◽  
Mei Jiang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Retrograde Transport ◽  
Striatal Dopamine ◽  
Dopamine Level ◽  
Expression Platform ◽  
Cargo Proteins ◽  
Vacuolar Protein ◽  
Golgi Network ◽  
Old Mice

AbstractVacuolar protein sorting 35 (VPS35) is a major component of the retromer complex that mediates the retrograde transport of cargo proteins from endosomes to the trans-Golgi network. Mutations such as D620N in the VPS35 gene have been identified in patients with autosomal dominant Parkinson’s disease (PD). However, it remains poorly understood whether and how VPS35 deficiency or mutation contributes to PD pathogenesis; specifically, the studies that have examined VPS35 thus far have differed in results and methodologies. We generated a VPS35 D620N mouse model using a Rosa26-based transgene expression platform to allow expression in a spatial manner, so as to better address these discrepancies. Here, aged (20-months-old) mice were first subjected to behavioral tests. Subsequently, DAB staining analysis of substantia nigra (SN) dopaminergic neurons with the marker for tyrosine hydroxylase (TH) was performed. Next, HPLC was used to determine dopamine levels, along with levels of its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum. Western blotting was also performed to study the levels of key proteins associated with PD. Lastly, autoradiography (ARG) evaluation of [3H]FE-PE2I binding to the striatal dopamine transporter DAT was carried out. We found that VPS35 D620N Tg mice displayed a significantly higher dopamine level than NTg counterparts. All results were then compared with that of current VPS35 studies to shed light on the disease pathogenesis. Our model allows future studies to explicitly control spatial expression of the transgene which would generate a more reliable PD phenotype.

scholarly journals Altered striatal dopamine levels in Parkinson’s disease VPS35 D620N mutant transgenic aged mice

2020 ◽  
Author(s):  
Sarivin Vanan ◽  
Xiaoxia Zeng ◽  
Sook Yoong Chia ◽  
Katarina Varnäs ◽  
Mei Jiang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Retrograde Transport ◽  
Striatal Dopamine ◽  
Dopamine Level ◽  
Expression Platform ◽  
Cargo Proteins ◽  
Vacuolar Protein ◽  
Golgi Network ◽  
Old Mice

Abstract Vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex that mediates the retrograde transport of cargo proteins from endosomes to the trans-Golgi network. Mutations such as D620N in the VPS35 gene have been identified in patients with autosomal dominant Parkinson’s disease (PD). However, it remains poorly understood whether and how VPS35 deficiency or mutation contributes to PD pathogenesis; specifically, the studies that have examined VPS35 thus far have differed in results and methodologies. We generated a VPS35 D620N mouse model using a Rosa26-based transgene expression platform to allow expression in a spatial manner, so as to better address these discrepancies. Here, aged (20-months-old) mice were first subjected to behavioral tests. Subsequently, DAB staining analysis of substantia nigra (SN) dopaminergic neurons with the marker for tyrosine hydroxylase (TH) was performed. Next, HPLC was used to determine dopamine levels, along with levels of its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum. Western blotting was also performed to study the levels of key proteins associated with PD. Lastly, autoradiography (ARG) evaluation of [3H]FE-PE2I binding to the striatal dopamine transporter DAT was carried out. We found that VPS35 D620N Tg mice displayed a significantly higher dopamine level than NTg counterparts. All results were then compared with that of current VPS35 studies to shed light on the disease pathogenesis. Our model allows future studies to explicitly control spatial expression of the transgene which would generate a more reliable PD phenotype.

scholarly journals Presynaptic autophagy is coupled to the synaptic vesicle cycle via ATG-9

2020 ◽  
Author(s):  
Sisi Yang ◽  
Daehun Park ◽  
Laura Manning ◽  
Sarah E. Hill ◽  
Mian Cao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Synaptic Vesicle ◽  
List Type ◽  
Trans Golgi Network ◽  
C Elegans ◽  
Vesicle Cycle ◽  
Golgi Network ◽  
Activity Dependent ◽  
Synaptic Vesicle Cycle

SummaryAutophagy is a cellular degradation pathway essential for neuronal health and function. Autophagosome biogenesis occurs at synapses, is locally regulated and increases in response to neuronal activity. The mechanisms that couple autophagosome biogenesis to synaptic activity remain unknown. In this study we determine that trafficking of ATG-9, the only transmembrane protein in the core autophagy pathway, links the synaptic vesicle cycle with autophagy. ATG-9 positive vesicles in C. elegans are generated from the trans-Golgi network via AP3-dependent budding, and delivered to presynaptic sites. At presynaptic sites, ATG-9 undergoes exo-endocytosis in an activity-dependent manner. Mutations that disrupt endocytosis, including one associated with Parkinson’s disease, result in abnormal ATG-9 accumulation at clathrin-rich synaptic foci and defects in activity-dependent presynaptic autophagy. Our findings uncover regulated key steps of ATG-9 trafficking at presynaptic sites, and provide evidence that ATG-9 exo-endocytosis couples autophagosome biogenesis at presynaptic sites with the activity-dependent synaptic vesicle cycle.HighlightsIn C. elegans, ATG-9 is delivered to presynaptic sites in vesicles generated from the trans-Golgi network via AP-3-dependent buddingATG-9 vesicles undergo activity-dependent exo-endocytosis at presynaptic sitesMutations in endocytic proteins, including a mutation associated with Parkinson’s disease, result in abnormal ATG-9 accumulation at clathrin-rich fociAbnormal accumulation of ATG-9 at clathrin-rich foci is associated with defects in activity-dependent presynaptic autophagy

scholarly journals Altered Striatal Dopamine Levels in Parkinson’s Disease VPS35 D620N Mutant Transgenic Aged Mice

2020 ◽  
Author(s):  
Sarivin Vanan ◽  
Xiaoxia Zeng ◽  
Sook Yoong Chia ◽  
Katarina Varnäs ◽  
Zhang Ke ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Retrograde Transport ◽  
Striatal Dopamine ◽  
Dopamine Level ◽  
Expression Platform ◽  
Cargo Proteins ◽  
Vacuolar Protein ◽  
Golgi Network ◽  
Old Mice

Abstract Vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex that mediates the retrograde transport of cargo proteins from endosomes to the trans-Golgi network. Mutations such as D620N in the VPS35 gene have been identified in patients with autosomal dominant Parkinson’s disease (PD). However, it remains poorly understood whether and how VPS35 deficiency or mutation contributes to PD pathogenesis; specifically, the studies that have examined VPS35 thus far have differed in results and methodologies. We generated a VPS35 D620N mouse model using a Rosa26-based transgene expression platform to allow expression in a spatial manner, so as to better address these discrepancies. Here, aged (20-months-old) mice were first subjected to behavioral tests. Subsequently, DAB staining analysis of substantia nigra (SN) dopaminergic neurons with the marker for tyrosine hydroxylase (TH) was performed. Next, HPLC was used to determine dopamine levels, along with levels of its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum. Western blotting was also performed to study the levels of key proteins associated with PD. Lastly, autoradiography (ARG) evaluation of [3H]FE-PE2I binding to the striatal dopamine transporter DAT was carried out. We found that VPS35 D620N Tg mice displayed a significantly higher dopamine level than NTg counterparts. All results were then compared with that of current VPS35 studies to shed light on the disease pathogenesis. Our model allows future studies to explicitly control spatial expression of the transgene which would generate a more reliable PD phenotype.

GGA proteins regulate retrograde transport of BACE1 from endosomes to the trans-Golgi network

2005 ◽  
Vol 29 (3) ◽  
pp. 453-461 ◽  
Author(s):  
Tina Wahle ◽  
Kai Prager ◽  
Nikolai Raffler ◽  
Christian Haass ◽  
Michael Famulok ◽  
...  
Keyword(s):  
Retrograde Transport ◽  
Trans Golgi Network ◽  
Golgi Network
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