An antiaggregation gene therapy strategy for Lewy body disease utilizing β-synuclein lentivirus in a transgenic model

Hashimoto, Makoto; Rockenstein, Edward; Mante, Michael; Crews, Leslie; Bar-On, Pazit; Gage, F. H.; Marr, Robert A.; Masliah, Eliezer

doi:10.1038/sj.gt.3302349

Cited by 93 publications

(89 citation statements)

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“…4 -6 Supporting this, overexpression of ␤-syn in ␣-syn transgenic mice by either crossing with ␤-syn transgenic mice or using lentivirus-mediated transfer results in amelioration of neuropathology. 4,6,7 Thus, these results suggest endogenous molecules that inhibit ␣-syn aggregation may have a therapeutic potential against synucleinopathies.…”

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confidence: 88%

Protective Role of Endogenous Gangliosides for Lysosomal Pathology in a Cellular Model of Synucleinopathies

Wei

Fujita

Nakai

et al. 2009

The American Journal of Pathology

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Gangliosides may be involved in the pathogenesis of Parkinson's disease and related disorders, although the precise mechanisms governing this involvement remain unknown. In this study, we determined whether changes in endogenous ganglioside levels affect lysosomal pathology in a cellular model of synucleinopathy. For this purpose, dementia with Lewy body-linked P123H ␤-synuclein (␤-syn) neuroblastoma cells transfected with ␣-synuclein were used as a model system because these cells were characterized as having extensive formation of lysosomal inclusions bodies. Treatment of these cells with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glycosyl ceramide synthase, resulted in various features of lysosomal pathology, including compromised lysosomal activity, enhanced lysosomal membrane permeabilization, and increased cytotoxicity. Consistent with these findings, expression levels of lysosomal membrane proteins, ATP13A2 and LAMP-2, were significantly decreased, and electron microscopy demonstrated alterations in the lysosomal membrane structures. Furthermore, the accumulation of both P123H ␤-syn and ␣-synuclein proteins was significant in PDMP-treated cells because of the suppressive effect of PDMP on the autophagy pathway. Finally, the detrimental effects of PDMP on lysosomal pathology were significantly ameliorated by the addition of gangliosides to the cultured cells. These data suggest that endogenous gangliosides may play protective roles against the lysosomal pathology of synucleinopathies. (Am J

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confidence: 88%

Protective Role of Endogenous Gangliosides for Lysosomal Pathology in a Cellular Model of Synucleinopathies

Wei

Fujita

Nakai

et al. 2009

The American Journal of Pathology

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“…Thus, therapeutic strategies for AD, PD, and FTD might require reducing the synthesis, preventing the aggregation and/or enhancing the clearance of Aβ, tau, or α-syn. Numerous strategies directed at reducing the accumulation of these proteins have been developed, including the use of small interfering RNA, antisense RNA [39][40][41][42][43], degrading enzymes (e.g., cathepsin D, neurosin, neprilysin) [44][45][46], chaperonelike molecules that modulate aggregation state (e.g., Hsp70, β-syn) [47][48][49][50], anti-aggregation compounds (e.g., polyphenols) [51][52][53], and immunotherapy (passive, active, and Tcell-based) [54]. Moreover, the recent discovery that toxic oligomeric forms of α-syn and tau accumulate in the plasma membrane and are secreted to the extracellular environment has provided further rationale for the development of immunotherapeutic approaches for PD, DLB, MSA, FTD, and other neurodegenerative disorders characterized by the abnormal accumulation of these proteins [24,26,[55][56][57][58].…”

Section: Introductionmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

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“…Immunoblot and Immunoprecipitation Analyses-Immunoblot analysis was performed as previously described (50). Briefly, cells were lysed in buffer A (20 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM EDTA, 1 mM NaVO 4 , 50 mM NaF, with protease inhibitors (Roche Applied Science)) containing 1% Triton X-100.…”

Section: Methodsmentioning

confidence: 99%

α-Synuclein Aggregates Interfere with Parkin Solubility and Distribution

Kawahara

Hashimoto

Bar-On

et al. 2008

Journal of Biological Chemistry

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Parkinson Disease (PD) 2 belongs to a group of heterogeneous movement disorders jointly named Lewy body disease (LBD) (1). These conditions are associated with progressive and selective loss of dopaminergic and non-dopaminergic cells (2) and the formation of Lewy bodies (LBs) and Lewy neurites, which contain fibrillar ␣-synuclein (␣-syn) (3-6).Although the identification and distribution of ␣-syn-immunoreactive LBs is a useful neuropathological marker for the diagnosis of PD and LBD (7-9), recent studies suggest that abnormal neuronal accumulation of ␣-syn oligomers and protofibrils (10 -12) might be centrally involved in the pathogenesis of the neurodegenerative process in these disorders. ␣-Synuclein is an abundant synaptic protein (13) that interacts with a variety of proteins (14, 15), including those involved in regulating the vesicular release of dopamine (16,17).While the cause of sporadic PD is still unclear, familial forms of PD have been linked to mutations in various genes including ␣-syn, parkin, DJ1, PTEN-induced kinase 1 (PINK1), and leucine-rich repeat kinase-2 (LRRK2) (18 -21). Missense mutations (A30P, A53T, and E46K) and multiplications in the ␣-syn gene (22, 23) that accelerate aggregation and toxic conversion of ␣-syn have been described in a few families with autosomal dominant PD (24). Mutations in parkin are the most common cause of familial parkinsonism (25-27). Several reports indicate that parkin functions as an E3 ubiquitin protein ligase and that familial-linked mutations in parkin disrupt its ligase activity (28, 29) and de-stabilize its ubiquitin-like domain (30). In sporadic forms of PD and LBD, parkin accumulates in the insoluble fraction (31). In addition to incorporating ubiquitin to a number of substrates (32) such as the aminoacyl tRNA synthetase cofactor p38/JTV-1 (p38), ␣-tubulin, cell division control-related protein-1 (CDCrel-1, also known as the septin, Sept5), glycosylated ␣-syn (33), Parkin-associated endothelin receptorlike receptor (Pael-R) (34), and synphilin-1, parkin ubiquitinates itself as an early step in its proteasome-mediated degradation process (29,35,36). Of these substrates, more recent studies in parkin knock-out mice have shown that p38 is the most important parkin substrate (37); however, p38 is unlikely to be a target of parkin-mediated degradation because a previous study showed that p38 is largely mono-ubiquitinated in the presence of parkin, and poly-ubiquitinated p38 is difficult to detect (38).Based on the genetic evidence and the known role of parkin as a ubiquitin ligase, most studies have focused at investigating the role of parkin alterations and proteasomal dysfunction on ␣-syn accumulation in the pathogenesis of PD (28, 39). However, recent evidence suggests that mutations (40) and stress

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An antiaggregation gene therapy strategy for Lewy body disease utilizing β-synuclein lentivirus in a transgenic model

Cited by 93 publications

References 50 publications

Protective Role of Endogenous Gangliosides for Lysosomal Pathology in a Cellular Model of Synucleinopathies

Protective Role of Endogenous Gangliosides for Lysosomal Pathology in a Cellular Model of Synucleinopathies

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

α-Synuclein Aggregates Interfere with Parkin Solubility and Distribution

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