The Role of VPS35 in the Pathobiology of Parkinson’s Disease

Sassone, Jenny; Reale, Chiara; Dati, Giovanna; Regoni, Maria; Pellecchia, Maria Teresa; Garavaglia, Barbara

doi:10.1007/s10571-020-00849-8

Cited by 38 publications

(36 citation statements)

References 98 publications

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“…This is in keeping with dysfunction of the ubiquitin proteosome system being central to neurodegeneration ( 74 , 75 ). VPS35 ( PARK17 ) has recently come to the fore as a cause of late-onset familial PD ( 76 ). How this gene contributes to human PD is unclear however it has been suggested that VPS35 mutations lead to mitochondrial dysfunction ( 77 ), and impaired lysosomal and autophagy function [for review see ( 76 )], all of which contribute to PD pathogenesis.…”

Section: Astrocytes and Their Role In Parkinson's Diseasementioning

confidence: 99%

“…VPS35 ( PARK17 ) has recently come to the fore as a cause of late-onset familial PD ( 76 ). How this gene contributes to human PD is unclear however it has been suggested that VPS35 mutations lead to mitochondrial dysfunction ( 77 ), and impaired lysosomal and autophagy function [for review see ( 76 )], all of which contribute to PD pathogenesis. To date the potential effects that mutations in either FBXO7 or VPS35 might have on astrocyte function remain unknown; further experiments would be required to elucidate this.…”

Section: Astrocytes and Their Role In Parkinson's Diseasementioning

confidence: 99%

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The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

et al. 2021

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Parkinson's disease (PD), the second most common neurodegenerative disease, is characterised by the motor symptoms of bradykinesia, rigidity and resting tremor and non-motor symptoms of sleep disturbances, constipation, and depression. Pathological hallmarks include neuroinflammation, degeneration of dopaminergic neurons in the substantia nigra pars compacta, and accumulation of misfolded α-synuclein proteins as intra-cytoplasmic Lewy bodies and neurites. Microglia and astrocytes are essential to maintaining homeostasis within the central nervous system (CNS), including providing protection through the process of gliosis. However, dysregulation of glial cells results in disruption of homeostasis leading to a chronic pro-inflammatory, deleterious environment, implicated in numerous CNS diseases. Recent evidence has demonstrated a role for peripheral immune cells, in particular T lymphocytes in the pathogenesis of PD. These cells infiltrate the CNS, and accumulate in the substantia nigra, where they secrete pro-inflammatory cytokines, stimulate surrounding immune cells, and induce dopaminergic neuronal cell death. Indeed, a greater understanding of the integrated network of communication that exists between glial cells and peripheral immune cells may increase our understanding of disease pathogenesis and hence provide novel therapeutic approaches.

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Section: Astrocytes and Their Role In Parkinson's Diseasementioning

confidence: 99%

Section: Astrocytes and Their Role In Parkinson's Diseasementioning

confidence: 99%

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

et al. 2021

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“…Considerable researches have demonstrated that VPS35 plays an important role in Parkinson’s disease [ 39 , 40 ]. Only one study showed that VPS35 promoted the proliferation of hepatoma cells through the PI3K/AKT signaling pathway [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

A novel autophagy-related genes prognostic risk model and validation of autophagy-related oncogene VPS35 in breast cancer

Cao

et al. 2021

Cancer Cell Int

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Background Accumulating evidence implies that autophagy plays a critical role in breast cancer development and progression. It is crucial to screen out autophagy-related encoding genes (ARGs) with prognostic value in breast cancer and reveal their biological properties in the aggressiveness of breast cancer. Methods Univariate and multivariate Cox proportional hazards analyses were used to identify a prognostic risk model of ARGs from The Cancer Genome Atlas (TCGA). Kaplan–Meier analysis, univariate and multivariate Cox regression analyses and receiver operating characteristic (ROC) curve analysis were performed to validate the risk model. Western blot and immunohistochemistry (IHC) were conducted to assess the expression of VPS35 (one of ARGs in risk model). CCK8, Colony formation assay, Transwell migration/invasion assays and autophagy flux assay were used to confirm biological function of VPS35 in breast cancer. Results In this study, the prognostic risk model consisting of six ARGs (VPS35, TRIM21, PRKAB2, RUFY4, MAP1LC3A and LARP1) in breast cancer were identified. The risk model was further verified as a novel independent prognostic factor for breast cancer patients. We also clarified that vacuolar protein sorting-associated protein 35 (VPS35), one of ARGs in the risk model, was upregulated in breast cancer samples and cell lines. VPS35 overexpression was correlated with more aggressive phenotype of breast cancer and indicated worse prognosis in both progression-free survival and overall survival analyses. Meanwhile, VPS35 knockdown inhibited breast cancer cell proliferation, migration and invasion, suggesting that VPS35 promoted the progression of breast cancer. VPS35 silence also influenced autophagy process, indicating that VPS35 was essential for autophagy completion. Conclusion Taken together, the six ARGs risk model has a remarkably prognostic value for breast cancer. Among them, VPS35 might exert as a significant oncogenic and prognostic factor for breast cancer and could be a promising autophagy-related therapeutic target in clinical practice.

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“…Hence, the D620N mutation in Vps35 rendered a loss-of-function effect on constraining viral propagation. Although their pathogenicity remains inconclusive, several other Vps35 variants are also segregated with PD [8]. It is possible that the pathogenicity of these variants may commence when recurrent viral infection occurs.…”

Section: Discussionmentioning

confidence: 99%

“…A small proportion of PD cases are inherited and arise from mutations in single genes [1,4], among which the vacuolar protein sorting 35 ortholog (Vps35) is linked to a rare, late-onset autosomal-dominant form of PD [5,6]. Although additional Vps35 variants are also segregated with PD, only the aspartate (D) to asparagine (N) mutation at residue 620 is found to be pathogenic [7,8]. Furthermore, Vps35 loss-of-of 21 function is involved in the pathogenesis of AD [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Parkinson’s Disease Causative Mutation in Vps35 Disturbs Tetherin Trafficking to Cell Surfaces and Facilitates Virus Spread

Ding

Chhetri

et al. 2021

Cells

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Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by progressive loss of dopaminergic neurons in the substantia nigra, intraneuronal deposition of misfolded proteins known as Lewy bodies, and chronic neuroinflammation. PD can arise from monogenic mutations, but in most cases, the etiology is unclear. Viral infection is gaining increasing attentions as a trigger of PD. In this study, we investigated whether the PD-causative 620 aspartate (D) to asparagine (N) mutation in the vacuolar protein sorting 35 ortholog (Vps35) precipitated herpes simplex virus (HSV) infection. We observed that ectopic expression of Vps35 significantly reduced the proliferation and release of HSV-1 virions; the D620N mutation rendered Vps35 a partial loss of such inhibitory effects. Tetherin is a host cell protein capable of restricting the spread of encapsulated viruses including HSV-1 and SARS-Cov-2, both of which are implicated in the development of parkinsonism. Compared with cells overexpressing wildtype Vps35, cells expressing mutant Vps35 with D620N had less Tetherin on cell surfaces. Real-time and static cell imaging revealed that Tetherin recycled through Vps35-positive endosomes. Expression of Vps35 with D620N reduced endosomal dynamics and frequency of motile Tetherin-containing vesicles, a sign of defective production of recycling carriers. Our study suggests that the D620N mutation in Vps35 hinders Tetherin trafficking to cell surfaces and facilitates virus spread.

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The Role of VPS35 in the Pathobiology of Parkinson’s Disease

Cited by 38 publications

References 98 publications

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

A novel autophagy-related genes prognostic risk model and validation of autophagy-related oncogene VPS35 in breast cancer

Parkinson’s Disease Causative Mutation in Vps35 Disturbs Tetherin Trafficking to Cell Surfaces and Facilitates Virus Spread

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