Retromer dependent changes in cellular homeostasis and Parkinson's disease

Yang, Zhe; Li, Zebin; Teasdale, Rohan D.

doi:10.1042/ebc20210023

Cited by 4 publications

(2 citation statements)

References 125 publications

(149 reference statements)

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“…On the other hand, as part of the SNX-BAR heterodimer which itself is part of the retromer, SNX5 was particularly interesting. It is known that the retromer plays a role in the pathophysiology of PD (19)(20)(21). Mutations in an important component of the retromer, VPS35, are risk factors to develop PD, but the frequency of such mutations is not yet known (22,23).…”

Section: Discussionmentioning

confidence: 99%

A genome-wide RNA interference screening reveals protectiveness of SNX5 knockdown in a Parkinson’s disease cell model

Höllerhage,

Duan,

Chua

et al. 2024

Preprint

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BackgroundAlpha-synuclein is a major player in the pathophysiology of a group of diseases called synucleinopathies, which include Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. To date, there is no disease-modifying therapy available for these synucleinopathies. Furthermore, the intracellular mechanisms by which alpha-synuclein confers toxicity are not yet fully understood. Therefore, it is of utmost importance to investigate the pathophysiology of alpha-synuclein-induced toxicity in order to identify novel molecular targets for the development of disease-modifying therapies.MethodsIn the present study, we performed the first genome-wide siRNA modifier screening in a human postmitotic neuronal cell model using alpha-synuclein-induced toxicity as read-out. In a multi-step approach, we identified several genes, whose knockdown protected from alpha-synuclein-induced toxicity. The main hit was further validated by different methods, including immunofluorescence microscopy, qPCR, and Western blot.ResultsThe highest protection was achieved by knockdown ofSNX5, which encodes the SNX5 protein, a component of the retromer complex. We confirmed the protective efficacy ofSNX5knockdown with an independent siRNA system. SNX5 protein is part of SNX-BAR heterodimers, which are part of the retromer complex. We found that extracellular and overexpressed intracellular alpha-synuclein led to fragmentation of the trans-Golgi network, which was prevented bySNX5knockdown by confining alpha-synuclein in early endosomes.ConclusionIn summary, our data suggest that SNX5 plays an important role in trafficking and toxicity of alpha-synuclein. Therefore, SNX5 appears to be a possible target for therapeutic interventions in synucleinopathies.

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Section: Discussionmentioning

confidence: 99%

A genome-wide RNA interference screening reveals protectiveness of SNX5 knockdown in a Parkinson’s disease cell model

Höllerhage,

Duan,

Chua

et al. 2024

Preprint

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“…The dimer formed by SNX5 is responsible for recruiting retromer into the endosome and is an essential protein involved in intracellular and intracellular material transport and signal transduction [ 16 , 22 ]. In recent years, genomics animal and cell biology have shown that retromer-mediated protein transport defects in endosomal sorting are closely related to PD pathogenesis [ 15 , 23 , 24 ]. SNXs play a variety of roles in different aspects of endosomal transport, including the transport of endosomes to the trans-Golgi network, circulation to the cell surface, and endocytosis [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Sorting Nexin 5 Plays an Important Role in Promoting Ferroptosis in Parkinson’s Disease

Huang

Han

et al. 2022

Oxidative Medicine and Cellular Longevity

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Parkinson’s disease (PD) is a common neurodegenerative disease in the elderly, which is related to brain iron metabolism disorders. Ferroptosis is a newly discovered iron-dependent programmed cell death mode, which has been considered an essential mechanism of PD pathogenesis in recent years. However, its underlying mechanisms have not been fully understood. In the present study, the PD rat model and PD cell model were induced by 6-hydroyxdopamine (6-OHDA). The results showed that the expression of Sorting Nexin 5 (SNX5) and the level of ferroptosis will increase after treatment with 6-OHDA. Consistent with these results, ferroptosis inducer erastin synergistically reduced the expression of glutathione peroxidase 4 (GPX4) and increased the expression of SNX5 in the PD cell model, while ferroptosis inhibitor ferrostatin-1 (Fer-1) inhibited the decrease of GPX4 and the increase of SNX5 in the PD cell model. Knockdown of SNX5 in PC-12 cells could reduce intracellular lipid peroxidation and accumulation of Fe2+ and significantly inhibit the occurrence of ferroptosis. In conclusion, the present study suggested that SNX5 promotes ferroptosis in the PD model, thus providing new insights and potential for research on the pharmacological targets of PD.

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Restoration of metal homeostasis: a potential strategy against neurodegenerative diseases

Zhang

Ren

et al. 2023

Ageing Research Reviews

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Retromer dependent changes in cellular homeostasis and Parkinson's disease

Cited by 4 publications

References 125 publications

A genome-wide RNA interference screening reveals protectiveness of SNX5 knockdown in a Parkinson’s disease cell model

A genome-wide RNA interference screening reveals protectiveness of SNX5 knockdown in a Parkinson’s disease cell model

Sorting Nexin 5 Plays an Important Role in Promoting Ferroptosis in Parkinson’s Disease

Restoration of metal homeostasis: a potential strategy against neurodegenerative diseases

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