Converging cellular themes for the hereditary spastic paraplegias

Abstract

Hereditary spastic paraplegias (HSPs) are neurologic disorders characterized by prominent lower-extremity spasticity, resulting from a length-dependent axonopathy of corticospinal upper motor neurons. They are among the most genetically-diverse neurologic disorders, with >80 distinct genetic loci and over 60 identified genes. Studies investigating the molecular pathogenesis underlying HSPs have emphasized the importance of converging cellular pathogenic themes in the most common forms of HSP, providing compelling targets for therapy. Most notably, these include organelle shaping and biogenesis as well as membrane and cargo trafficking.

Figure 1

Human pyramidal motor system, emphasizing the long corticospinal neurons affected in HSP. Adapted from [1].

Figure 2

Common pathogenic themes in the HSPs, emphasizing where the listed proteins are known or believed to function (adapted from [1]). Some proteins in Table 1 are not listed, pending further studies of their main sites of action.

Figure 3

Diagram of an axon, emphasizing organelle interactions with the cytoskeleton (top) and with one another (bottom). Though not shown, multiple motor types can be found on the same organelle.