The genetic cause of SMA is deletion of the SMN 1 gene affecting Survival Motor Neurone (SMN) expression, but precisely how low or reduced levels of SMN lead to SMA is not properly understood. Efforts to decipher the complex cellular pathology of SMA are complicated by the fact that the SMN protein has numerous functions within the cell; an additional and poorly understood phenomenon is that while it is thought that many cell types are affected in SMA, motor neurons appear particularly sensitive to low levels of SMN protein.
SMN has been implicated in transport of mRNA in neural cells for local translation. We previously identified microtubule-dependant mobile vesicles rich in SMN and the splicing factor SmB, a member of the Sm protein family, in neural cells. By comparing the proteome of SmB to that of SmN, a neural-specific Sm protein, we have shown that the essential neural protein neurochondrin (NCDN) interacts with Sm proteins and SMN in the context of mobile vesicles in neurites. NCDN has roles in protein localisation in neural cells, and in maintenance of cell polarity. NCDN is required for the correct localisation of SMN, suggesting they may both be required for formation and transport of trafficking vesicles.
NCDN provides a potential therapeutic target for SMA together with, or in place of, those targeting SMN expression.Therapeutics increasing NCDN expression could prove useful in treating SMA, and we have developed NCDN modulators for use in the treatment and/or prevention of spinal muscular atrophy.