Thioredoxin‐interacting protein induced α‐synuclein accumulation via inhibition of autophagic flux: Implications for Parkinson's disease

Su, Cunjin; Yu, Feng; Liu, Tengteng; Liu, Xu; Bao, Junjie; Shi, Aiming; Hu, Duanmin; Liu, Tong; Yu, Yunli

doi:10.1111/cns.12721

Cited by 47 publications

(33 citation statements)

References 34 publications

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“…The LRKK2 hMO also contained higher levels of phosphorylated α-syn in endosomal compartments, and higher expression levels of markers of mitophagy and autophagy. The authors also identified TXNIP [a thiol-oxidoreductase that induces lysosomal dysfunction and DA cell death when overexpressed ( 78 )] as an important mediator of LRRK2 -G2019S pathological mechanisms, and proved that knocking-down its expression reversed the accumulation of phosphorylated α-syn.…”

Section: Modeling Pd In Vitromentioning

confidence: 99%

Patient-Derived Midbrain Organoids to Explore the Molecular Basis of Parkinson's Disease

2020

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Induced pluripotent stem cell-derived organoids offer an unprecedented access to complex human tissues that recapitulate features of architecture, composition and function of in vivo organs. In the context of Parkinson's Disease (PD), human midbrain organoids (hMO) are of significant interest, as they generate dopaminergic neurons expressing markers of Substantia Nigra identity, which are the most vulnerable to degeneration. Combined with genome editing approaches, hMO may thus constitute a valuable tool to dissect the genetic makeup of PD by revealing the effects of risk variants on pathological mechanisms in a representative cellular environment. Furthermore, the flexibility of organoid co-culture approaches may also enable the study of neuroinflammatory and neurovascular processes, as well as interactions with other brain regions that are also affected over the course of the disease. We here review existing protocols to generate hMO, how they have been used so far to model PD, address challenges inherent to organoid cultures, and discuss applicable strategies to dissect the molecular pathophysiology of the disease. Taken together, the research suggests that this technology represents a promising alternative to 2D in vitro models, which could significantly improve our understanding of PD and help accelerate therapeutic developments.

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Section: Modeling Pd In Vitromentioning

confidence: 99%

Patient-Derived Midbrain Organoids to Explore the Molecular Basis of Parkinson's Disease

2020

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“…Subcutaneous ASC is easily accessible from patents and it can be engineered ex-vivo, expanded, and transplanted subcutaneously in its own environment without provoking immune responses. In addition to diabetes, TXNIP is also known to be upregulated in age-related neurodegenerative diseases such as Alzhemer’s and Parkinson’s diseases and Amyotrophic lateral sclerosis (ALS) [22,23]. In these neuronal diseases, mitochondrial dysfunction, protein misfolding and mitophagy deregulation are known to be critically involved in pathogenesis.…”

Section: Resultsmentioning

confidence: 99%

Gene and Tissue Engineering For the Treatment of Diabetes and Its Retinal Complications: The Use of Nucleic Acid Constructs Bearing A TXNIP Gene Promoter

Singh

2018

CTBEB

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Diabetes is a chronic disease in which insulin production is deficient (Type 1) or resistant (Type 2) leading to organ complications including the heart, kidney, retina, and peripheral nerves. About 10% of diabetics are Type 1 while ~90 percent are Type 2 associated with life style changes and obesity. Whether it is Type 1 or Type 2, chronic hyperglycemia prevails and associated oxidative stress and low grade inflammation are considered to play critical roles in diabetes and its complications including diabetic retinopathy (DR). Thioredoxin-Interacting Protein, TXNIP, is strongly induced by diabetes and high glucose in all tissues examined including the pancreatic beta cells and the retina. TXNIP binds to and inhibits the anti-oxidant and thiol reducing capacity of thioredoxins and causes cellular oxidative stress, inflammation and premature cell death. TXNIP is induced strongly by high glucose and its metabolites with minutes and remains elevated as long as hyperglycemia persists. Therefore, the TXNIP gene promoter linked with insulin or a gene of interest may be used to induce gene expression or suppression and in tissue engineering for adipose or tissue-derived autologous stem cells producing insulin for the treatment of diabetes and its complications such as DR as well as age-related neurodegenerative diseases.

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“…The localization of ATP13A2 within the lysosomal membrane implies that it plays a role in modulating autophagy [ 26 ]; therefore, we analyzed human colon cancer specimens. We found that low expression levels of ATP13A2 are closely related to high expression levels of LC3 and SQSTM1, both of which are degraded by lysosomal acid phosphatase following the fusion of the autophagosome with the lysosome.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Parkinson’s disease-related gene ATP13A2 reduces tumorigenesis via blocking autophagic flux in colon cancer

et al. 2020

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Background Accumulating evidence shows that Parkinson’s disease is negatively associated with colon cancer risk, indicating that Parkinson’s disease family proteins may be involved in the initiation of colon cancer. Here, we aimed to identify a Parkinson’s disease-related gene involved in colon cancer, elucidate the underlying mechanisms, and test whether it can be used as a target for cancer therapy. Methods We first screened colon cancer and normal tissues for differential expression of Parkinson’s disease-associated genes and identified ATP13A2, which encodes cation-transporting ATPase 13A2, as a putative marker for colon cancer. We next correlated ATP13A2 expression with colon cancer prognosis. We performed a series of ATP13A2 knockdown and overexpression studies in vitro to identify the contribution of ATP13A2 in the stemness and invasive capacity of colon cancer cells. Additionally, autophagy flux assay were determined to explore the mechanism of ATP13A2 induced stemness. Finally, we knocked down ATP13A2 in mice using siRNA to determine whether it can be used as target for colon cancer treatment. Results Colon cancer patients with high ATP13A2 expression exhibit shorter overall survival than those with low ATP13A2. Functionally, ATP13A2 acts as a novel stimulator of stem-like traits. Furthermore, knockdown of ATP13A2 in HCT116 resulted in decreased levels of cellular autophagy. Additionally, bafilomycin A1, an autophagy inhibitor, reversed the ATP13A2-induced stemness of colon cancer cells. Lastly treatment with ATP13A2 siRNA reduced the volume of colon cancer xenografts in mice. Conclusions The PD-associated gene ATP13A2 is involved in colon cancer stemness through regulation of autophagy. Furthermore, ATP13A2 is a novel prognostic biomarker for colon cancer and is a potential target for colon cancer therapy.

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Thioredoxin‐interacting protein induced α‐synuclein accumulation via inhibition of autophagic flux: Implications for Parkinson's disease

Abstract: Our data suggested that TXNIP blocked autophagic flux and induced α-synuclein accumulation through inhibition of ATP13A2, indicating TXNIP was a disease-causing protein in PD.

Cited by 47 publications

References 34 publications

Patient-Derived Midbrain Organoids to Explore the Molecular Basis of Parkinson's Disease

Patient-Derived Midbrain Organoids to Explore the Molecular Basis of Parkinson's Disease

Gene and Tissue Engineering For the Treatment of Diabetes and Its Retinal Complications: The Use of Nucleic Acid Constructs Bearing A TXNIP Gene Promoter

Knockdown of Parkinson’s disease-related gene ATP13A2 reduces tumorigenesis via blocking autophagic flux in colon cancer

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