Alpha Synuclein: Tau in PD
A majority of the focus surrounds α-synuclein in PD therapy, however, tau shows promise as a neuroprotective target. Tau is a protein, located in neuronal cells, that stabilizes and promotes the assembly of microtubules (Witman et al., 1976). There are six different human isoforms of Tau, each containing microtubule binding repeat motifs that mediate axonal transport (Lei et al., 2010). The ability of this protein to bind its targets depends on posttranslational modifications: phosphorylation, glycosylation, and acetylation (Iba et al., 2013).
There are pathogenic interactions between α-synuclein and tau that result in the development of PD. In neurodegenerative disorders, like Alzheimer’s and Parkinson’s, tau is hyperphosphorylated causing microtubule destabilization and hindered protein transport leading to protein accumulation of insoluble neurofibrillary tangles (NFTs) in the cell body of neurons. Additionally, Tau is a constituent of LB and LN that interacts with α-synuclein; the simultaneous phosphorylation of both tau and α-synuclein suggests a pathophysiological function (Lei et al., 2010).
There has been an abundance of research analyzing how the interactions of α-synuclein and tau contribute to PD. In an early study, Jensen et al. (1999) showed that α-synuclein increases Tau phosphorylation at Ser262/356. Then, 11 years later, similar results were found when human neuroblastoma M17 cells were exposed to MPTP; intracellular α-synuclein phosphorylated Tau at Ser262. α-synuclein was described as an “in vivo” regulator of tau, and tau as a major factor in the chain of events that lead to the death of dopamine neurons in the brain (Qureshi et al., 2010). The purpose of this recruitment and phosphorylation could be to aid in the neurodegenerative procession; α-synuclein induced phosphorylation of tau destabilizes microtubules causing a lowered rate of axonal transport. Damage to the machinery that conducts the cellular delivery of proteins, including α-synuclein, results in the accumulation and deposition of the aggregates, leading to neurodegeneration (De Vos et al., 2008).