Down-regulating α-synuclein for treating synucleopathies

Abstract

Extensive cell loss in the substantia nigra pars compacta and widespread aggregation of the a-synuclein (a-syn) protein in the form of Lewy bodies (LB) and Lewy neurites are neuropathological hallmarks of Parkinson’s disease (PD). Over the past two decades, a myriad of studies have suggested a significant pathogenic role of a-syn in both familial and sporadic forms of PD, as well as in other synucleinopathies, such as dementia with Lewy bodies and multiple system atrophy. Although the mechanisms driving neurodegeneration remain unclear, a number of teams have already started developing therapeutic strategies aimed at blocking neuronal death that target a-syn under various conditions. Based on current knowledge of a-syn–induced cell death in PD, targeting a-syn could thus aim at reducing (1) the overall expression level, such as at the transcription or translation steps, (2) the levels of specific posttranslationally modified species (eg, phosphorylated, nitrated, oxidized, or truncated forms), or (3) the levels of specific aggregated forms (eg, monomers, oligomers, protofibrils, fibrils, and so forth). Because a-syn handling and clearance may contribute to PD pathogenesis, boosting its degradation both by the ubiquitin-proteasome system and by the autophagy/lysosomal pathway is also a tantalizing possibility. The observation of a “host-to-thegraft” transmission of LB pathology in the human brain led to the speculation that cell-to-cell transmission of abnormal a-syn species may contribute to PD pathogenesis. Such spreading also offers an alternate therapeutic option by blocking a-syn transfer between cells, an unforeseen possible effect of immunization therapies. Although a-syn has rapidly become the subject of intensive research for diagnosis purpose, it has also been considered, despite our limited knowledge of PD pathophysiology, as a therapeutic target with approaches ranging from anti-aggregation compounds and gene silencing approaches to clearance strategies. Given the relationship between a-syn burden and pathology, the first move would be to downregulate a-syn expression through the reduction of the expression. In the current issue of Movement Disorders, Cooper et al. adopt this concept and circumvent the usual roadblock of gene therapy, that is, the delivery of the construct to the entire brain, by using targeted exosomes carrying a-syn small interference (si)RNA for successfully down-regulating a-syn in normal mice as well as in a transgenic mouse model expressing the phospho-mimic human S129D a-syn complementary DNA under the control of the prion (PrP) promoter (PrP-hSNCA-HA). Their results are of interest to Movement Disorders readers for several reasons: First, the delivery method, previously used for the targeted silencing of b-site APP cleaving enzyme I and glyceraldehyde 3-phosphate dehydrogenase, allows systemic delivery of a nucleic acid to the entire brain. The technology is based on the encapsulation of the nucleic acid construct into exosomes. Exosomes are small membrane vesicles (40-120 nm in diameter) of endocytic origin released by several cell types found extracellularly in tissues but also in fluids (including urine). Those exosomes, being natural carriers of nucleic acids and proteins between cells, are a perfect cargo for siRNAs. Moreover, their size enables crossing the blood–brain barrier after systemic delivery, making the administration of the gene therapy easier compared with stereotaxic administration of more conventional vectors. Once inside the brain, the targeting of those exosomes to cells is achieved through the expression at the surface of the exosome of a braintargeting peptide, the rabies virus glycoprotein peptide (RVG), in the extra-exosomal part of an abundant protein constituent of the exosomal membrane, Lamp2b. Second, the intravenously administered a-syn siRNA RVG-exosomes are capable of reducing the endogenous -----------------------------------------------------------*Correspondence to: Dr. Erwan Bezard, Institut des Maladies Neurod eg en eratives, Universit e de Bordeaux, UMR 5293, Bât 3B 1er etage, 146 rue L eo Saignat, 33076 Bordeaux cedex, France, E-mail: erwan.bezard@u-bordeaux.fr