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1.
Int J Mol Sci ; 23(15)2022 Jul 27.
Article in English | MEDLINE | ID: mdl-35955451

ABSTRACT

The presence of protein inclusions, called Lewy bodies (LBs) and Lewy neurites (LNs), in the brain is the main feature of Parkinson's disease (PD). Recent evidence that the prion-like propagation of α-synuclein (α-syn), as a major component of LBs and LNs, plays an important role in the progression of PD has gained much attention, although the molecular mechanism remains unclear. In this study, we evaluated whether neuronal ApoE regulates the cell-to-cell transmission of α-syn and explored its molecular mechanism using in vitro and in vivo model systems. We demonstrate that neuronal ApoE deficiency attenuates both α-syn uptake and release by downregulating LRP-1 and LDLR expression and enhancing chaperone-mediated autophagy activity, respectively, thereby contributing to α-syn propagation. In addition, we observed that α-syn propagation was attenuated in ApoE knockout mice injected with pre-formed mouse α-syn fibrils. This study will help our understanding of the molecular mechanisms underlying α-syn propagation.


Subject(s)
Apolipoproteins E/metabolism , Parkinson Disease , alpha-Synuclein/metabolism , Animals , Apolipoproteins E/genetics , Lewy Bodies/metabolism , Mice , Neurons/metabolism , Parkinson Disease/genetics , Parkinson Disease/metabolism , alpha-Synuclein/genetics
3.
EMBO Rep ; 21(7): e48950, 2020 07 03.
Article in English | MEDLINE | ID: mdl-32372484

ABSTRACT

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons located in the substantia nigra pars compacta and the presence of proteinaceous inclusions called Lewy bodies and Lewy neurites in numerous brain regions. Increasing evidence indicates that Lewy pathology progressively involves additional regions of the nervous system as the disease advances, and the prion-like propagation of α-synuclein (α-syn) pathology promotes PD progression. Accordingly, the modulation of α-syn transmission may be important for the development of disease-modifying therapies in patients with PD. Here, we demonstrate that α-syn fibrils induce c-src activation in neurons, which depends on the FcγRIIb-SHP-1/-2-c-src pathway and enhances signals for the uptake of α-syn into neurons. Blockade of c-src activation inhibits the uptake of α-syn and the formation of Lewy body-like inclusions. Furthermore, the blockade of c-src activation also inhibits the release of α-syn via activation of autophagy. The brain-permeable c-src inhibitor, saracatinib, efficiently reduces α-syn propagation into neighboring regions in an in vivo model system. These results suggest a new therapeutic target against progressive PD.


Subject(s)
Parkinson Disease , alpha-Synuclein , Brain/metabolism , Dopaminergic Neurons/metabolism , Humans , Lewy Bodies/metabolism , Parkinson Disease/genetics , alpha-Synuclein/genetics , alpha-Synuclein/metabolism
4.
Exp Neurobiol ; 27(5): 377-386, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30429647

ABSTRACT

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme that is highly expressed in neurons, and gathering evidence indicates that UCH-L1 may play pathogenic roles in many neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease (PD). Additionally, lipid rafts have attracted interest in neurodegeneration as playing a common role in many neurodegenerative diseases. In the present study, we demonstrated that UCH-L1 associates with lipid rafts as with other PD-associated gene products. In addition, UCH-L1 regulates lipid raft-dependent endocytosis and it is not dependent on the expression and degradation of caveolin-1 or flotillin-1. Finally, UCH-L1 regulates cell-to-cell transmission of α-synuclein. This study provides evidence that many PD-associated gene products share common signaling pathways to explain the pathogenesis of PD.

5.
Cell Rep ; 22(1): 136-148, 2018 01 02.
Article in English | MEDLINE | ID: mdl-29298416

ABSTRACT

Recent evidence of prion-like propagation of α-synuclein (α-syn) into neighboring neurons set up a paradigm to elucidate the mechanism of progression of Parkinson's disease (PD) and to develop therapeutic strategies. Here, we show that FcγRIIB expressed in neurons functions as a receptor for α-syn fibrils and mediates cell-to-cell transmission of α-syn. SHP-1 and 2 are activated downstream by α-syn fibrils through FcγRIIB and play an important role in cell-to-cell transmission of α-syn. Also, taking advantage of a co-culture system, we show that cell-to-cell transmission of α-syn induces intracellular Lewy body-like inclusion body formation and that the FcγRIIB/SHP-1/2 signaling pathway is involved in it. Therefore, the FcγRIIB-SHP-1/-2 signaling pathway may be a therapeutic target for the progression of PD. The in vitro system is an efficient tool for further high-throughput screening that can be used for developing a therapeutic intervention in PD.


Subject(s)
Neurons/metabolism , Parkinson Disease/metabolism , Prions , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Receptors, IgG/metabolism , Signal Transduction , alpha-Synuclein/metabolism , Cell Line , Humans , Neurons/pathology , Parkinson Disease/genetics , Parkinson Disease/pathology , Protein Transport/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics , Receptors, IgG/genetics , alpha-Synuclein/genetics
6.
Mol Neurodegener ; 10: 63, 2015 Dec 01.
Article in English | MEDLINE | ID: mdl-26627850

ABSTRACT

BACKGROUND: Parkinson's disease (PD) is characterized by progressive loss of midbrain dopaminergic neurons, resulting in motor dysfunctions. While most PD is sporadic in nature, a significant subset can be linked to either autosomal dominant or recessive mutations. PARK2, encoding the E3 ubiquitin ligase, parkin, is the most frequently mutated gene in autosomal recessive early onset PD. It has recently been reported that PD-associated gene products such as PINK1, α-synuclein, LRRK2, and DJ-1, as well as parkin associate with lipid rafts, suggesting that the dysfunction of these proteins in lipid rafts may be a causal factor of PD. Therefore here, we examined the relationship between lipid rafts-related proteins and parkin. RESULTS: We identified caveolin-1 (cav-1), which is one of the major constituents of lipid rafts at the plasma membrane, as a substrate of parkin. Loss of parkin function was found to disrupt the ubiquitination and degradation of cav-1, resulting in elevated cav-1 protein level in cells. Moreover, the total cholesterol level and membrane fluidity was altered by parkin deficiency, causing dysregulation of lipid rafts-dependent endocytosis. Further, cell-to-cell transmission of α-synuclein was facilitated by parkin deficiency. CONCLUSIONS: Our results demonstrate that alterations in lipid rafts by the loss of parkin via cav-1 may be a causal factor of PD, and cav-1 may be a novel therapeutic target for PD.


Subject(s)
Caveolin 1/genetics , Endocytosis/physiology , Membrane Microdomains/metabolism , Mutation/genetics , Parkinson Disease/metabolism , Ubiquitin-Protein Ligases/genetics , Animals , Caveolin 1/metabolism , Dopaminergic Neurons/metabolism , Mice , Parkinson Disease/genetics , alpha-Synuclein/metabolism
7.
Neurobiol Dis ; 83: 90-9, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26342897

ABSTRACT

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. Although the etiology of PD has not yet been fully understood, accumulating evidence indicates that neuroinflammation plays a critical role in the progression of PD. α-Synuclein (α-Syn) has been considered to be a key player of the pathogenesis of PD, and recent reports that prion-like propagation of misfolded α-syn released from neurons may play an important role in the progression of PD have led to increased attention to the studies elucidating the roles of extracellular α-syn in the CNS. Extracellular α-syn has also been reported to regulate microglial inflammatory response. In this study, we demonstrated that aggregated α-syn inhibited microglial phagocytosis by activating SHP-1. SHP-1 activation was also observed in A53T α-syn transgenic mice. In addition, aggregated α-syn bound to FcγRIIB on microglia, inducing SHP-1 activation, further inhibiting microglial phagocytosis. Aggregated α-syn upregulated FcγRIIB expression in microglia and upregulated FcγRIIB was also observed in A53T α-syn transgenic mice. These data suggest that aggregated α-syn released from neurons dysregulates microglial immune response through inhibiting microglial phagocytosis, further causing neurodegeneration observed in PD. The interaction of aggregated α-syn and FcγRIIB and further SHP-1 activation can be a new therapeutic target against PD.


Subject(s)
Brain/metabolism , Microglia/metabolism , Microglia/physiology , Phagocytosis , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Receptors, IgG/metabolism , alpha-Synuclein/metabolism , Animals , Cells, Cultured , Mice , Mice, Inbred C57BL , Mice, Transgenic , Protein Aggregates/physiology , Rats , Rats, Sprague-Dawley
8.
Proc Natl Acad Sci U S A ; 111(27): 9911-6, 2014 Jul 08.
Article in English | MEDLINE | ID: mdl-24958862

ABSTRACT

Noise-induced hearing loss is one of the most common types of sensorineural hearing loss. In this study, we examined the expression and localization of leukotriene receptors and their respective changes in the cochlea after hazardous noise exposure. We found that the expression of cysteinyl leukotriene type 1 receptor (CysLTR1) was increased until 3 d after noise exposure and enhanced CysLTR1 expression was mainly observed in the spiral ligament and the organ of Corti. Expression of 5-lipoxygenase was increased similar to that of CysLTR1, and there was an accompanying elevation of CysLT concentration. Posttreatment with leukotriene receptor antagonist (LTRA), montelukast, for 4 consecutive days after noise exposure significantly decreased the permanent threshold shift and also reduced the hair cell death in the cochlea. Using RNA-sequencing, we found that the expression of matrix metalloproteinase-3 (MMP-3) was up-regulated after noise exposure, and it was significantly inhibited by montelukast. Posttreatment with a MMP-3 inhibitor also protected the hair cells and reduced the permanent threshold shift. These findings suggest that acoustic injury up-regulated CysLT signaling in the cochlea and cochlear injury could be attenuated by LTRA through regulation of MMP-3 expression. This study provides mechanistic insights into the role of CysLTs signaling in noise-induced hearing loss and the therapeutic benefit of LTRA.


Subject(s)
Cochlea/injuries , Cysteine/metabolism , Disease Models, Animal , Leukotrienes/metabolism , Noise/adverse effects , Signal Transduction , Acetates/therapeutic use , Animals , Cyclopropanes , Gene Expression Profiling , Leukotriene Antagonists/therapeutic use , Matrix Metalloproteinase 3/metabolism , Mice , Quinolines/therapeutic use , Receptors, Leukotriene/drug effects , Sulfides , Wounds and Injuries/drug therapy , Wounds and Injuries/etiology
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