REEPing the benefits of an animal model of hereditary spastic paraplegia

Abstract

The hereditary spastic paraplegias (HSPs) are characterized by spasticity of the leg muscles due to axonal degeneration of corticospinal neurons. Beetz et al. report that the core motor phenotype and axonal pathology of HSPs are recapitulated in mice lacking the HSP-associated gene Reep1. REEP1 is shown to regulate ER structure in motor cortex neurons. The Reep1 knockout mouse should be a very useful model in which to study the mechanisms of progressive axon loss in HSPs and other disorders.

Figure 1. Schematic illustration of a corticospinal neuron in wild-type (Reep1^+/+) and knockout (Reep1^–/–) mice.

In the knockout mouse, there is distal loss of the primary axon to the spinal cord; the status of the collateral axon to the striatum is unknown. In addition, the ER tubules in the mutant mouse are fewer in number and longer than those seen in the wild-type mouse. The inserts illustrate the effect of REEP1 on ER membrane curvature. In wild-type mice, membrane α-helices of REEP1 (yellow) are inserted into the outer leaflet of the ER membrane, promoting curvature, with a cytosolic C-terminal microtubule-binding domain (orange). In Reep1^–/– mice, the lack of REEP1 protein results in more planar ER membranes. As a result, ER membranes appear much longer in electron micrographs of thin sections. The lack of ER membrane curvature is hypothesized to disrupt vesicular trafficking along microtubules in long corticospinal axons of motoneurons in Reep1^–/– mice, resulting in progressive retrograde axonal degeneration.