miRNA and antisense oligonucleotide-based α-synuclein targeting as disease-modifying therapeutics in Parkinson’s disease

Abstract

α-synuclein is the synaptic protein majorly involved in neuronal dysfunction and death and it is well known for the last two decades as a hallmark of Parkinson’s disease. Alpha-synuclein is involved in neurodegeneration mediated through various neurotoxic pathways, majorly including autophagy or lysosomal dysregulation, mitochondrial disruption, synaptic dysfunction, and oxidative stress. Moreover, the alpha-synuclein aggregation has been associated with the development of several neurodegenerative conditions such as various forms of Parkinson’s disease. The recent discovery in oligonucleotide chemistry has developed potential alpha-synuclein targeting molecules for the treatment of neurodegenerative diseases. The present review article focuses on recent advances in the applications of oligonucleotides acting via alpha-synuclein targeting mechanisms and their implication in combating Parkinson’s disease. Moreover, the article emphasizes the potential of miRNAs, and antisense oligonucleotides and the challenges associated with their use in the therapeutical management of Parkinson’s disease.

NeuronalSNCAtranscription during Lewy body formation

“…Many studies support the notion that accumulation of misfolded α-syn drives disease pathogenesis ('proteinopathy') [1, 2, 4-9, 11, 15, 20, 21]. Therefore, α-syn is currently a major therapeutic target for synucleinopathies, for example by eliminating pathological aggregates by monoclonal α-syn antibodies, by inhibiting α-syn aggregation, or by stabilizing α-syn monomers, or by directly targeting SNCA gene expression with miRNA and antisense oligonucleotide therapies, amongst others [22][23][24]. However, it has been argued that the lack of physiological protein (referred to as 'proteinopenia') is a major contributor to the neurodegeneration in LBD [25], supported in part by the absence of notable impact in recent clinical trials involving monoclonal α-syn antibodies [22,23].…”