Dataset Information

?-synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease.

ABSTRACT:

Objective

Progressive accumulation of ?-synuclein (?-syn) has been associated with Parkinson's disease (PD) and Dementia with Lewy body (DLB). The mechanisms through which ?-syn leads to neurodegeneration are not completely clear; however, the formation of various oligomeric species have been proposed to play a role. Antibody therapy has shown effectiveness at reducing ?-syn accumulation in the central nervous system (CNS); however, most of these studies have been conducted utilizing antibodies that recognize both monomeric and higher molecular weight ?-syn. In this context, the main objective of this study was to investigate the efficacy of immunotherapy with single-chain antibodies (scFVs) against specific conformational forms of ?-syn fused to a novel brain penetrating sequence.

Method

We screened various scFVs against ?-syn expressed from lentiviral vectors by intracerebral injections in an ?-syn tg model. The most effective scFVs were fused to the cell-penetrating peptide penetratin to enhance transport across the blood-brain barrier, and lentiviral vectors were constructed and tested for efficacy following systemic delivery intraperitoneal into ?-syn tg mice.

Result

Two scFVs (D5 and 10H) selectively targeted different ?-syn oligomers and reduced the accumulation of ?-syn and ameliorated functional deficits when delivered late in disease development; however, only one of the antibodies (D5) was also effective when delivered early in disease development. These scFVs were also utilized in an enzyme-linked immunosorbent assay (ELISA) assay to monitor the effects of immunotherapy on ?-syn oligomers in brain and plasma.

Interpretation

The design and targeting of antibodies for specific species of ?-syn oligomers is crucial for therapeutic immunotherapy and might be of relevance for the treatment of Lewy body disease.

SUBMITTER: Spencer B

PROVIDER: S-EPMC4999592 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Publications

α-synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease.

Spencer Brian B Williams Stephanie S Rockenstein Edward E Valera Elvira E Xin Wei W Mante Michael M Florio Jazmin J Adame Anthony A Masliah Eliezer E Sierks Michael R MR

Annals of clinical and translational neurology 20160616 8

<h4>Objective</h4>Progressive accumulation of α-synuclein (α-syn) has been associated with Parkinson's disease (PD) and Dementia with Lewy body (DLB). The mechanisms through which α-syn leads to neurodegeneration are not completely clear; however, the formation of various oligomeric species have been proposed to play a role. Antibody therapy has shown effectiveness at reducing α-syn accumulation in the central nervous system (CNS); however, most of these studies have been conducted utilizing ant ...[more]

PMID: 27606342

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Project description:Autosomal dominant variants in LRP10 have been identified in patients with Lewy body diseases (LBDs), including Parkinson's disease (PD), Parkinson's disease-dementia (PDD), and dementia with Lewy bodies (DLB). Nevertheless, there is little mechanistic insight into the role of LRP10 in disease pathogenesis. In the brains of control individuals, LRP10 is typically expressed in non-neuronal cells like astrocytes and neurovasculature, but in idiopathic and genetic cases of PD, PDD, and DLB, it is also present in α-synuclein-positive neuronal Lewy bodies. These observations raise the questions of what leads to the accumulation of LRP10 in Lewy bodies and whether a possible interaction between LRP10 and α-synuclein plays a role in disease pathogenesis. Here, we demonstrate that wild-type LRP10 is secreted via extracellular vesicles (EVs) and can be internalised via clathrin-dependent endocytosis. Additionally, we show that LRP10 secretion is highly sensitive to autophagy inhibition, which induces the formation of atypical LRP10 vesicular structures in neurons in human-induced pluripotent stem cells (iPSC)-derived brain organoids. Furthermore, we show that LRP10 overexpression leads to a strong induction of monomeric α-synuclein secretion, together with time-dependent, stress-sensitive changes in intracellular α-synuclein levels. Interestingly, patient-derived astrocytes carrying the c.1424 + 5G > A LRP10 variant secrete aberrant high-molecular-weight species of LRP10 in EV-free media fractions. Finally, we show that this truncated patient-derived LRP10 protein species (LRP10splice) binds to wild-type LRP10, reduces LRP10 wild-type levels, and antagonises the effect of LRP10 on α-synuclein levels and distribution. Together, this work provides initial evidence for a possible functional role of LRP10 in LBDs by modulating intra- and extracellular α-synuclein levels, and pathogenic mechanisms linked to the disease-associated c.1424 + 5G > A LRP10 variant, pointing towards potentially important disease mechanisms in LBDs.