Dysfunction of two lysosome degradation pathways of α-synuclein in Parkinson’s disease: potential therapeutic targets?

Jiang, Tianfang; Chen, Shengdi

doi:10.1007/s12264-012-1263-1

Cited by 14 publications

(9 citation statements)

References 39 publications

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“…α-Syn, a small synaptic protein and the primary component of Lewy bodies, if incorrectly modified or misfolded, can form soluble or insoluble aggregates and act as the neuropathological hallmark in the brain of patients with either sporadic or familial PD ( 54 ). α-Syn plays a leading role in the initiation and progression of Parkinson-like neurodegeneration because it can induce high neurotoxicity by diverse pathways, such as inflammation, oxidative stress and autophagy abnormalities ( 54 , 55 ). The neurotoxicity of α-syn is largely attributed to its soluble or insoluble aggregates of oligomers or polymers, which are found throughout the SNpc in PD but are also found in other neurons.…”

Section: Pathogenic Protein Function In Autoimmunity-associated Pdmentioning

confidence: 99%

The Challenge of the Pathogenesis of Parkinson's Disease: Is Autoimmunity the Culprit?

Jiang

et al. 2018

Front. Immunol.

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The role of autoimmunity in Parkinson's disease (PD), as one of the most popular research subjects, has been intensively investigated in recent years. Although the ultimate cause of PD is unknown, one major area of interest remains identifying new therapeutic targets and options for patients suffering from PD. Herein, we present a comprehensive review of the impacts of autoimmunity in neurodegenerative diseases, especially PD, and we have composed a logical argument to substantiate that autoimmunity is actively involved in the pathogenesis of PD through several proteins, including α-synuclein, DJ-1, PINK1, and Parkin, as well as immune cells, such as dendritic cells, microglia, T cells, and B cells. Furthermore, a detailed analysis of the relevance of autoimmunity to the clinical symptoms of PD provides strong evidence for the close correlation of autoimmunity with PD. In addition, the previously identified relationships between other autoimmune diseases and PD help us to better understand the disease pattern, laying the foundation for new therapeutic solutions to PD. In summary, this review aims to integrate and present currently available data to clarify the pathogenesis of PD and discuss some controversial but innovative research perspectives on the involvement of autoimmunity in PD, as well as possible novel diagnostic methods and treatments based on autoimmunity targets.

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Section: Pathogenic Protein Function In Autoimmunity-associated Pdmentioning

confidence: 99%

The Challenge of the Pathogenesis of Parkinson's Disease: Is Autoimmunity the Culprit?

Jiang

et al. 2018

Front. Immunol.

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“…Abating proteostatic stress in PD, where both chaperone-mediated autophagic and macro-autophagic systems are perturbed and changes in cellular oxidation accelerate misfolding, may be a complementary clinical target to α-syn toxicity. 5 , 30 , 33 , 34 …”

Section: Discussionmentioning

confidence: 99%

Proteasome-targeted nanobodies alleviate pathology and functional decline in an α-synuclein-based Parkinson’s disease model

Chatterjee

Bhatt

Butler

et al. 2018

npj Parkinson's Disease

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Therapeutics designed to target α-synuclein (α-syn) aggregation may be critical in halting the progression of pathology in Parkinson’s disease (PD) patients. Nanobodies are single-domain antibody fragments that bind with antibody specificity, but allow readier genetic engineering and delivery. When expressed intracellularly as intrabodies, anti-α-syn nanobodies fused to a proteasome-targeting proline, aspartate or glutamate, serine, and threonine (PEST) motif can modulate monomeric concentrations of target proteins. Here we aimed to validate and compare the in vivo therapeutic potential of gene therapy delivery of two proteasome-directed nanobodies selectively targeting α-syn in a synuclein overexpression-based PD model: VH14*PEST (non-amyloid component region) and NbSyn87*PEST (C-terminal region). Stereotaxic injections of adeno-associated viral 5-α-syn (AAV5-α-syn) into the substantia nigra (SN) were performed in Sprague–Dawley rats that were sorted into three cohorts based on pre-operative behavioral testing. Rats were treated with unilateral SN injections of vectors for VH14*PEST, NbSyn87*PEST, or injected with saline 3 weeks post lesion. Post-mortem assessments of the SN showed that both nanobodies markedly reduced the level of phosphorylated Serine-129 α-syn labeling relative to saline-treated animals. VH14*PEST showed considerable maintenance of striatal dopaminergic tone in comparison to saline-treated and NbSyn87*PEST-treated animals as measured by tyrosine hydroxylase immunoreactivity (optical density), DAT immunoreactivity (optical density), and dopamine concentration (high-performance liquid chromatography). Microglial accumulation and inflammatory response, assessed by stereological counts of Iba-1-labeled cells, was modestly increased in NbSyn87*PEST-injected rats but not in VH14*PEST-treated or saline-treated animals. Modest behavioral rescue was also observed, although there was pronounced variability among individual animals. These data validate in vivo therapeutic efficacy of vector-delivered intracellular nanobodies targeting α-syn misfolding and aggregation in synucleinopathies such as PD.

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“…On the other side, impaired degradation pathways responsible for α-synuclein may also be compromised in PD [ 9 , 10 ]. Almost all major known degradation pathways have been implicated in the degradation of α-synuclein [ 11 , 12 ], particularly, autophagy and proteasomal pathways are considered to play key roles in the process [ 13 , 14 , 15 ], in which both ubiquitin-proteasome system [ 16 , 17 ] and the autophagy-lysosomal pathway were confirmed to degrade α-synuclein [ 9 , 18 ]. Moreover, the chaperone-mediated autophagy (CMA) is also involved in wild-type α-synuclein degradation in PC12 and SH-SY5Y cells [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Targeted Suppression of Chaperone-Mediated Autophagy by miR-320a Promotes α-Synuclein Aggregation

Yang

Zhu

et al. 2014

IJMS

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Chaperone-mediated autophagy (CMA) is involved in wild-type α-synuclein degradation in Parkinson’s disease (PD), and LAMP2A and Hsc 70 have recently been indicated to be deregulated by microRNAs. To recognize the regularory role of miR-320a in CMA and the possible role in α-synuclein degradation, in the present study, we examined the targeting and regulating role of miR-320 in Hsc 70 expression. We first constructed an α-synuclein-overexpressed human neuroblastoma cell line, SH-SY5Y-Syn(+), stably over-expressing wild-type α-synuclein and sensitive to an autophagy inhibitor, which exerted no effect on the expression of LAMP2A and Hsc 70. Then we evaluated the influence on the CMA by miR-320a in the SH-SY5Y-Syn(+) cells. It was shown that miR-320a mimics transfection of specifically targeted Hsc 70 and reduced its expression at both mRNA and protein levels, however, the other key CMA molecule, LAMP2A was not regulated by miR-320a. Further, the reduced Hsc 70 attenuated the α-synuclein degradation in the SH-SY5Y-Syn(+) cells, and induced a significantly high level of α-synuclein accumulation. In conclusion, we demonstrate that miR-320a specifically targeted the 3' UTR of Hsc 70, decreased Hsc 70 expression at both protein and mRNA levels in α-synuclein-over-expressed SH-SY5Y cells, and resulted in significant α-synuclein intracellular accumulation. These results imply that miR-320a might be implicated in the α-synuclein aggravation in PD.

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Dysfunction of two lysosome degradation pathways of α-synuclein in Parkinson’s disease: potential therapeutic targets?

Cited by 14 publications

References 39 publications

The Challenge of the Pathogenesis of Parkinson's Disease: Is Autoimmunity the Culprit?

The Challenge of the Pathogenesis of Parkinson's Disease: Is Autoimmunity the Culprit?

Proteasome-targeted nanobodies alleviate pathology and functional decline in an α-synuclein-based Parkinson’s disease model

Targeted Suppression of Chaperone-Mediated Autophagy by miR-320a Promotes α-Synuclein Aggregation

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