Alpha Synuclein: Synuclein Family
Potential Targets in the Synuclein Family
The synuclein family consists of three small, soluble proteins; α, β, and ƴ-synuclein. Each contain a conserved alpha-helical lipid-binding motif and is expressed in neural tissue and certain tumours of vertebrates. α and β are found mainly in the brain, while ƴ is found in the peripheral nervous system. The normal functions of these proteins are unknown; however, some hypothesize that they mediate membrane stability and turnover (George, 2002).
Mutations in α-synuclein have been heavily associated with Parkinson’s disease as the protein constitutes LBs and LNs. The β and ƴ-synucleins are not located in LBs or LNs, but they are linked to hippocampal axon pathology in Parkinson’s disease (Galvin et al., 1999). Therefore, β and ƴ-synucleins, may be potential targets in PD therapy.
β-synuclein shares 60% sequence identity with α-synuclein, however, it is not currently a primary target in PD therapy. β-synuclein is fibril resistant under normal cytoplasmic conditions, however, the protein was reported to undergo a toxic gain of function mutation in response to changes in cytosolic pH and produce β-synuclein fibrils. At a pH of 5.8, β-synuclein fibrilization begins to occur (Moriarty et al., 2017), which opens up the possibility of targeting β-synuclein in PD treatment.
The synucleins, additionally, seem to work together to uphold the PD phenotype (Senior et al., 2008). α-synuclein is known to regulate dopamine, therefore knocking out this protein should lead to higher dopamine levels in the cell. Yet, mice missing any one synuclein protein fail to exhibit improved dopamine levels and a change in the disease phenotype, perhaps due to the other synuclein proteins pathogenically compensating for the absence. Therefore, knocking out or inhibiting gamma and beta synuclein as well as α-synuclein, could be a method of restoring dopamine levels in PD treatment.