Brain disposition of α-Synuclein: roles of brain barrier systems and implications for Parkinson’s disease

Bates, Christopher A.; Zheng, Wei

doi:10.1186/2045-8118-11-17

Cited by 39 publications

(33 citation statements)

References 56 publications

(90 reference statements)

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“…9). The specificity is further supported by the unique fact that the assembly of these two disordered hallmarks occurs exclusively at pathological conditions since in normal brain SYN and TPPP/p25 are expressed in neurons [57,58] and oligodendrocytes [9,59], respectively. Previously we showed that TPPP/p25, similarly to SYN, could be taken up by cells from the medium [35].…”

Section: Discussionmentioning

confidence: 82%

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Szénási¹,

Oláh²,

Szabó³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The hallmarks of Parkinson's disease and other synucleinopathies, Tubulin Polymerization Promoting Protein (TPPP/p25) and α-synuclein (SYN) have two key features: they are disordered and co-enriched/co-localized in brain inclusions. These Neomorphic Moonlighting Proteins display both physiological and pathological functions due to their interactions with distinct partners. To achieve the selective targeting of the pathological TPPP/p25-SYN but not the physiological TPPP/ p25-tubulin complex, their interfaces were identified as a specific innovative strategy for the development of anti-Parkinson drugs. Therefore, the interactions of TPPP/p25 with tubulin and SYN were characterized which suggested the involvements of the 178-187 aa and 147-156 aa segments in the complexation of TPPP/p25 with tubulin and SYN, respectively. However, various truncated and deletion mutants reduced but did not abolish the interactions except one mutant; in addition synthetized fragments corresponding to the potential binding segments of TPPP/p25 failed to interact with SYN. In fact, the studies of the multiple interactions at molecular and cellular levels revealed the high conformational plasticity, chameleon feature, of TPPP/p25 that ensures exceptional functional resilience; the lack of previously identified binding segments could be replaced by other segments. The experimental results are underlined by distinct bioinformatics tools. All these data revealed that although targeting chameleon proteins is a challenging task, nevertheless, the validation of a drug target can be achieved by identifying the interface of complexes of the partner proteins existing at the given pathological conditions.

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Section: Discussionmentioning

confidence: 82%

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Szénási¹,

Oláh²,

Szabó³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Alpha-synuclein is expressed in the rat CP, primary culture of CP cells and an immortalized line of rat CP epithelial cells (Z310). This indicates that the CP can transport alpha-synuclein between the blood and CSF [256,257]. However, this transport mechanism is not fully understood and needs further examination.…”

Section: Parkinson's Diseasementioning

confidence: 99%

Choroid plexus and the blood–cerebrospinal fluid barrier in disease

Solar

Zamani

Kubíčková

et al. 2020

Fluids Barriers CNS

174

142

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The choroid plexus (CP) forming the blood-cerebrospinal fluid (B-CSF) barrier is among the least studied structures of the central nervous system (CNS) despite its clinical importance. The CP is an epithelio-endothelial convolute comprising a highly vascularized stroma with fenestrated capillaries and a continuous lining of epithelial cells joined by apical tight junctions (TJs) that are crucial in forming the B-CSF barrier. Integrity of the CP is critical for maintaining brain homeostasis and B-CSF barrier permeability. Recent experimental and clinical research has uncovered the significance of the CP in the pathophysiology of various diseases affecting the CNS. The CP is involved in penetration of various pathogens into the CNS, as well as the development of neurodegenerative (e.g., Alzheimer´s disease) and autoimmune diseases (e.g., multiple sclerosis). Moreover, the CP was shown to be important for restoring brain homeostasis following stroke and trauma. In addition, new diagnostic methods and treatment of CP papilloma and carcinoma have recently been developed. This review describes and summarizes the current state of knowledge with regard to the roles of the CP and B-CSF barrier in the pathophysiology of various types of CNS diseases and sets up the foundation for further avenues of research. Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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“…These transport properties, however, have yet to be thoroughly investigated at the BCSFB or BBB. For detailed discussions, please see a recent review by Bates and Zheng [19]. …”

Section: Introductionmentioning

confidence: 99%

Expression and Transport of a-Synuclein at the Blood-Cerebrospinal Fluid Barrier and Effects of Manganese Exposure

Bates

Ysselstein

et al. 2015

ADMET DMPK

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The choroid plexus maintains the homeostasis of critical molecules in the brain by regulating their transport between the blood and cerebrospinal fluid (CSF). The current study was designed to investigate the potential role of the blood-CSF barrier (BCSFB) in α-synuclein (a-Syn) transport in the brain as affected by exposure to manganese (Mn), the toxic metal implicated in Parkinsonian disorders. Immunohistochemistry was used to identify intracellular a-Syn expression at the BCSFB. Quantitative real-time PCR was used to quantify the change in a-Syn mRNA expression following Mn treatments at the BCSFB in vitro. ELISA was used to quantify a-Syn levels following in vivo and in vitro treatments of Mn, copper (Cu), and/or external a-Syn. Thioflavin-T assay was used to investigate a-Syn aggregation after incubating with Mn and/or Cu in vitro. A two-chamber Transwell system was used to study a-Syn transport by BCSFB monolayer. Data revealed the expression of endogenous a-Syn in rat choroid plexus tissue and immortalized choroidal epithelial Z310 cells. The cultured primary choroidal epithelia from rats showed the ability to take up a-Syn from extracellular medium and transport a-Syn across the cellular monolayer from the donor to receiver chamber. Exposure of cells with Mn induced intracellular a-Syn accumulation without causing any significant changes in a-Syn mRNA expression. A significant increase in a-Syn aggregation in a cell-free system was observed with the presence of Mn. Moreover, Mn exposure resulted in a significant uptake of a-Syn by primary cells. These data indicate that the BCSFB expresses a-Syn endogenously and is capable of transporting a-Syn across the BCSFB monolayer; Mn exposure apparently increases a-Syn accumulation in the BCSFB by facilitating its uptake and intracellular aggregation.

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Brain disposition of α-Synuclein: roles of brain barrier systems and implications for Parkinson’s disease

Cited by 39 publications

References 56 publications

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Choroid plexus and the blood–cerebrospinal fluid barrier in disease

Expression and Transport of a-Synuclein at the Blood-Cerebrospinal Fluid Barrier and Effects of Manganese Exposure

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