Abstract
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders with a global burden of approximately 6.1 million patients. Alpha-synuclein has been linked to both the sporadic and familial forms of the disease. Moreover, alpha-synuclein is present in Lewy-bodies, the neuropathological hallmark of PD, and the protein and its aggregation have been widely linked to neurotoxic pathways that ultimately lead to neurodegeneration. Such pathways include autophagy/lysosomal dysregulation, synaptic dysfunction, mitochondrial disruption, and endoplasmic reticulum (ER) and oxidative stress. Alpha-synuclein has not only been shown to alter cellular pathways but also to spread between cells, causing aggregation in host cells. Therapeutic approaches will need to address several, if not all, of these angles of alpha-synuclein toxicity. Here we review the current advances in therapeutic efforts for PD that aim to produce a disease-modifying therapy by targeting the spread, production, aggregation, and degradation of alpha-synuclein. These include: receptor blocking strategies whereby putative alpha-synuclein receptors could be blocked inhibiting alpha-synuclein spread, an alpha-synuclein reduction which will decrease the amount alpha-synuclein available for aggregation and pathway disruption, the use of small molecules in order to target alpha-synuclein aggregation, immunotherapy and the increase of alpha-synuclein degradation by increasing autophagy/lysosomal flux. The research discussed here may lead to a disease-modifying therapy that tackles disease onset and progression in the future.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, after Alzheimer’s Disease, and the most common movement disorder (Mhyre et al, 2012)
We examine advances in our current understanding of the pivotal role of αsyn in PD pathogenesis, including pathways implicated in αsyn toxicity, suggested seeding and propagation mechanisms that underlie cell-to-cell transmission between neighboring neurons, and viability of potential disease-modifying therapeutics targeted against pathological α-syn species
Through injection of αsyn preformed fibrils (PFFs) into the striatum of transgenic mice, researchers demonstrated the development of Lewy pathology, nigrostriatal degeneration, and importantly expanded our understanding of cell-to-cell transmission by describing the nature of spread in neuroanatomically connected regions: this provided the first evidence that synthetic α-syn PFFs alone can induce the initiation and propagation of α-syn pathology in vivo (Luk et al, 2012)
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, after Alzheimer’s Disease, and the most common movement disorder (Mhyre et al, 2012). We examine advances in our current understanding of the pivotal role of αsyn in PD pathogenesis, including pathways implicated in αsyn toxicity, suggested seeding and propagation mechanisms that underlie cell-to-cell transmission between neighboring neurons, and viability of potential disease-modifying therapeutics targeted against pathological α-syn species.
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