UC San Diego

Stathmin-2 (also known as SCG10) is encoded by one of the most abundantly expressed mRNAs in human motor neurons and is required for axonal regeneration after axotomy in cultured human motor neurons. It has long been associated with growth, maintenance, and homeostasis of neuronal axons. This function is believed to be due to stathmin-2’s ability to bind to two α/β-tubulin heterodimers and correspondingly to affect microtubule dynamics. Moreover, in almost all instances of the fatal, paralytic motor neuron disease ALS, stathmin-2 encoding mRNAs are suppressed in motor neurons as a consequence of missplicing STMN2 pre-mRNA through a mechanism directly dependent on nuclear loss of the RNA binding protein TDP-43. Restoration of stathmin-2 is sufficient to rescue axonal regeneration capacity after axotomy injury in human motor neurons depleted of TDP-43. Stathmin-2 has also been previously correlated with axon regeneration in vivo – multiple investigators have found both mRNA and protein levels increase specifically after injury in the nervous system in instances where regeneration is occurring. Here I show that stathmin-2, despite being a tubulin binding partner in vitro, does not play a major role in microtubule levels or assembly in cultured motor neurons; in fact, I show that the tubulin binding ability of stathmin-2 is not required for axon regeneration of axons in such neurons. I also show that stathmin-2 is transported in fast axonal transport in a tubulin-binding-independent, palmitoylation-dependent manner, and that it can be transported in groups of ~4 round stathmin-2-positive compartments within the axon. It does not co-localize or co-transport with any known canonical axonal cargo marker, but is co-transported with NMNAT2, a protein implicated in the DLK-dependent signaling pathway and Wallerian degeneration (as is stathmin-2). I also demonstrate that stathmin-2 is required for axon regeneration of motor axons in the murine nervous system, with half the normal level of stathmin-2 sufficient for full restoration of regeneration capability. Indeed, absence of stathmin-2 led to an apparent abundant degeneration of axons within the sciatic nerve at sites distal to the injury site, while for wild-type and heterozygous mice those markers were relatively less abundant. Thus, while the molecular events and partners through which stathmin-2 maintains axonal health and innervation capability, my evidence establishes that restoration of stathmin-2 levels represents an attractive therapeutic target not only for ALS and other TDP-43 proteinopathies, but possibly even for acute injuries of the nervous system.