Alpha-synuclein facilitates to form short unconventional microtubules that have a unique function in the axonal transport

Although alpha-synuclein (alpha Syn) has been linked to Parkinson's disease (PD), the mechanisms underlying the causative role in PD remain unclear. We previously proposed a model for a transportable microtubule (tMT), in which dynein is anchored to a short tMT by LIS1 followed by the kinesindependent anterograde transport; however the mechanisms that produce tMTs have not been determined. Our in vitro investigations of microtubule (MT) dynamics revealed that alpha Syn facilitates the formation of short MTs and preferentially binds to MTs carrying 14 protofilaments (pfs). Live-cell imaging showed that alpha Syn co-transported with dynein and mobile beta III-tubulin fragments in the anterograde transport. Furthermore, bi-directional axonal transports are severely affected in alpha Syn and gamma Syn depleted dorsal root ganglion neurons. SR-PALM analyses further revealed the fibrous co-localization of alpha Syn, dynein and beta III-tubulin in axons. More importantly, 14-pfs MTs have been found in rat femoral nerve tissue, and they increased approximately 19 fold the control in quantify upon nerve ligation, indicating the unconventional MTs are mobile. Our findings indicate that alpha Syn facilitates to form short, mobile tMTs that play an important role in the axonal transport. This unexpected and intriguing discovery related to axonal transport provides new insight on the pathogenesis of PD.