Alpha-synuclein is a protein that forms a major component of abnormal neuronal aggregates known as Lewy bodies. A particular group of neurodegenerative disorders (NDs) is characterized by the abnormal accumulation of α-synuclein; termed the α-synucleinopathies, this group includes Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Lysosomal storage diseases have also been linked to α-synuclein toxicity. Several therapeutic targets have been chosen among steps of metabolism of α-synuclein. Reducing α-synuclein synthesis or expression and increasing the clearance can be achieved in many ways. The development of immunotherapeutic approaches targeting α-synuclein has received considerable attention in recent years. The aim of this chapter is to present the α-synucleinopathies, as well as to present the most recent researches about treatment of synucleinopathies based on knowledge of the pathophysiology of α-synuclein pathways.
TopIntroduction
A common feature among a number of neurological disorders is the abnormal aggregation of a protein as observed with amyloid beta in Alzheimer’s disease (Selkoe et al., 1990) and huntingtin protein in Huntington’s disease (Vonsattel et al., 2011). In 1912, Frederick Lewy first described the cytoplasmic inclusions now known as Lewy bodies in the substantia nigra in PD Cortical Lewy bodies were first reported in association with dementia in 1961 (Okazaki et al., 1961) but they were felt to be a relatively rare finding until the 1980s, when first ubiquitin and later α-synuclein immunostains made it easier to see them (Spillantini et al., 1997) and demonstrated that Lewy bodies were a common neuropathologic finding in dementia (Gomperts, 2016). α-Synucleinopathies is a particular group of NDs characterized by the abnormal accumulation of α-synuclein (Gomperts, 2016; Kahle, 2008) (Figure 1). Lysosomal storage diseases have also been linked to α-synuclein toxicity (Wong and Krainc, 2017). There are new treatments being researched based on the pathophysiology of alpha-synuclein, and immunology. The aim of this chapter is to present the α-synucleinopathies, as well as to present the most recent researches about treatment of synucleinopathies based on knowledge of the pathophysiology of α-synuclein pathways.
Figure 1. Main common features among α-synucleinopathies
TopAlpha Synuclein
There are different strains of α-synuclein, defined as conformational variants of α-synuclein — that exhibit distinct properties such as differences in structure and toxicity and ability to seed, propagate and cross-seed tau fibrillization. α-synuclein is able to transition between multiple different conformations, including monomers, tetramers, higher-level oligomers (soluble conformations), fibrils (highly ordered insoluble conformations characterized by β-sheet conformation) and aggregates. In addition, differences in α-synuclein strains also exist between synucleinopathies, such as PD and MSA (Bendor et al., 2013; Wong and Krainc, 2017).
The presynaptic location of α-synuclein has been recognized since its original identification as a protein associated with synaptic vesicles (Maroteaux et al., 1988). The protein is relatively specific to the nervous system (Iwai et al., 1995). In addition, α-synuclein is widely expressed by many neuronal populations within both central and peripheral nervous systems, suggesting a general role in neuronal function. However, α-synuclein appears to be one of the last proteins that localizes to developing synapses, arriving after integral membrane proteins of the synaptic vesicle and the peripheral membrane synapsin proteins (Withers et al., 1997).