Effects of Mutant Alpha-Synuclein In the Activation of Retrograde Fast Axonal Transport

Parkinson’s disease (PD) is a progressive movement disorder affecting motor functions regulated by nigrostriatal pathway. Pathologically, PD is characterized by selective loss of dopaminergic neurons in substantia nigra and by the presence of intraneuronal protein aggregates called Lewy Bodies (LBs). α-synuclein(α-Syn), the major component of LBs is a 140 aa presynaptic protein implicated in synaptic function of neurons, but its role in PD pathogenesis is not completely understood. Autosomal missense mutations or duplication/triplication in α-Syn gene have been shown to cause familial forms of PD (fPD). Genetic evidence suggests that mutations in α-Syn induce a gain of function toxic to neurons, but the underlying mechanisms remain unknown. Interestingly, we found the fPD-related α-Syn mutant A30P abnormally activated retrograde fast axonal transport (rFAT) mediated by a Src Family kinase (SFKs)- Protein kinase Cµ (PKCμ) regulatory pathway, suggesting that the rFAT alteration might represent a critical component of PD pathogenesis. In this research, we proposed two specific aims to evaluate effects of pathogenic forms of α-Syn in the abnormal activation of rFAT. As a result, we observed that A30P α-Syn dramatically increases SFKs autophosphorylation during the activation of rFAT in squid axoplasm. In rat primary neurons, overexpression of pathogenic α-Syn shows slight increase in SFKs autophosphorylation only at early time course. Furthermore, both WT and A30P exhibited activating effect on SFKs autophosphorylation and activity in vitro, suggesting that there might be further unknown cell biological factors for A30P specific activation of SFKs. When rat primary neurons were stimulated by neurotrophin, SFKs and PKCμ mediated DIC phosphorylation, indicating SFKs and PKCμ are critical regulators for the molecular event associated with rFAT activation in neurons. However, overexpression of pathogenic forms of α-Syn did not represent significant result linked to rFAT activation. Here, we showed our observations suggesting the role of pathogenic α-Syn in the molecular events underlying the activation of rFAT, which is expected to provide better understanding of early events during PD pathogenesis.