ESCRT-mediated Uptake and Degradation of Brain-targeted α-synuclein Single Chain Antibody Attenuates Neuronal Degeneration In Vivo

Spencer, Brian; Emadi, Sharareh; Desplats, Paula; Eleuteri, Simona; Michael, Sarah; Kosberg, Kori; Shen, Jay; Rockenstein, Edward; Patrick, Christina; Adame, Anthony; González, Tania Rosado; Sierks, Michael R.; Masliah, Eliezer

doi:10.1038/mt.2014.129

Cited by 81 publications

(116 citation statements)

References 50 publications

(108 reference statements)

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“…These results are in agreement with our recent studies utilizing brain penetrant single chain antibodies that showed that clones capable of detecting α-syn oligomers were more effective at reducing synucleinopathy in tg when compared to single chain antibodies that had higher affinity for α-syn monomers (Spencer et al, 2014; Spencer et al, 2016). The advantage of the single chain antibodies in this study was the specificity and the ability to cross the blood brain barrier and as such they represent an important proof of principle.…”

Section: Discussionsupporting

confidence: 92%

“…Therefore, we developed single chain antibodies targeting α-syn oligomers and fibrils expressed from lentiviral vectors (Price et al, 2016; Spencer et al, 2014; Spencer et al, 2016). Although promising, there were some limitations, which led to the development of highly specific monoclonal antibodies differentially targeting oligomers versus fibrils.…”

Section: Introductionmentioning

confidence: 99%

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Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy

El-Agnaf

Overk

Rockenstein

et al. 2017

Neurobiology of Disease

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Disorders with progressive accumulation of α-synuclein (α-syn) are a common cause of dementia and parkinsonism in the aging population. Accumulation and propagation of α-syn play a role in the pathogenesis of these disorders. Previous studies have shown that immunization with antibodies that recognize C-terminus of α-syn reduces the intra-neuronal accumulation of α-syn and related deficits in transgenic models of synucleinopathy. These studies employed antibodies that recognize epitopes within monomeric and aggregated α-syn that were generated through active immunization or administered via passive immunization. However, it is possible that more specific effects might be achieved with antibodies recognizing selective species of the α-syn aggregates. In this respect we recently developed antibodies that differentially recognized various oligomers (Syn-O1, -O2, and -O4) and fibrilar (Syn-F1 and -F2) forms of α-syn. For this purpose wild-type α-syn transgenic (line 61) mice were immunized with these 5 different antibodies and neuropathologically and biochemically analyzed to determine which was most effective at reducing α-syn accumulation and related deficits. We found that Syn-O1, -O4 and -F1 antibodies were most effective at reducing accumulation of α-syn oligomers in multiple brain regions and at preventing neurodegeneration. Together this study supports the notion that selective antibodies against α-syn might be suitable for development new treatments for synucleinopathies such as PD and DLB.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy

El-Agnaf

Overk

Rockenstein

et al. 2017

Neurobiology of Disease

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“…The expressions of the striatal Tlr2 and the α-synuclein accumulation were also decreased by injection of LV-sh.TLR2 (data not shown). The α-Syn tg mice showed astrogliosis and microglia activation (Kim et al, 2013; Spencer et al, 2014), and delivery of LV-sh.TLR2 significantly decreased both microglia activation and astrogliosis in this model (Figures 4A, 4D, and 4E). Similar to our previous results, immunohistochemical analysis showed that expression of Tlr2 was increased in the α-Syn tg mice compared to non-tg mice (Kim et al, 2013) (Figures 4A, 4B, and S4D).…”

Section: Resultsmentioning

confidence: 99%

Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy

et al. 2015

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SUMMARY Impaired autophagy has been implicated in many neurodegenerative diseases, such as Parkinson's disease (PD), and might be responsible for deposition of aggregated proteins in neurons. However, little is known how neuronal autophagy and clearance of aggregated proteins are regulated. Here, we show a role for Toll-like receptor 2 (TLR2), a pathogen-recognizing receptor in innate immunity, in regulation of neuronal autophagy and clearance of α-synuclein, a protein aggregated in synucleinopathies, including PD. Activation of TLR2 resulted in accumulation of α-synuclein aggregates in neurons as a result of inhibition of autophagic activity through regulation of the AKT/mTOR pathway. In contrast, inactivation of TLR2 resulted in autophagy activation and increased clearance of neuronal α-synuclein, hence reduced neurodegeneration, in transgenic mice and in in vitro models. These results uncover novel roles of TLR2 in regulating neuronal autophagy, and the TLR2 pathway may be targeted for the autophagy activation strategies in treating neurodegenerative disorders.

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“…scFvs retain antigen-binding properties and can be easily screened for desired affinities using phage display methodology. Using this type of approach, scFvs that detect individual conformational species of α-syn have been identified [151][152][153], and could be potentially used to discriminate among protein conformers for the differential treatment of synucleinopathies or for diagnostic purposes [154]. Moreover, scFvs can be further modified to increase BBB penetrability and facilitate the clearance of α-syn.…”

Section: Developing New Technologies For Immunotherapymentioning

confidence: 99%

“…In this sense, a fusion protein comprising a scFv against α-syn plus the low density lipoprotein domain of apolipoprotein B was recently studied in a transgenic model of DLB. The braintargeted fusion antibody easily crosses the BBB and gets internalized by neurons using the endosomal sorting complexes required for transport (ESCRT) pathway for enhanced degradation of α-syn aggregates [151], thus attenuating neuronal degeneration in vivo. Similarly, a fusion protein comprising a scFv and a specific protease can further aid in the clearance of aggregation-prone proteins [155].…”

Section: Developing New Technologies For Immunotherapymentioning

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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ESCRT-mediated Uptake and Degradation of Brain-targeted α-synuclein Single Chain Antibody Attenuates Neuronal Degeneration In Vivo

Cited by 81 publications

References 50 publications

Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy

Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy

Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy

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

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