Axonal transport in hereditary spastic paraplegia

Voluntary movement relies on the pyramidal motor system that extends from the cerebral motor cortex to neuromuscular junctions. Corticospinal neurons are among the longest in the body, as their axons measure up to 1 m in length. Complex intracellular mechanisms are required for the axonal transport of organelles and other molecules over such long distances. In fact, defects in axon transport caused by mutation in the specific genes involved in axon transport give rise to hereditary spastic paraplegias (HSPs). HSPs are uncommon, with a prevalence of 5/100,000, and patients generally complain of frequent falls, stiff legs, cramps and unstable gait. Disease progression is usually slow but several patients end up requiring the assistance of canes, walkers or wheelchairs.

We are interested in the role of CPT1C in axon transport because we have recently described the presence of R37C CPT1C mutation in HSP-affected individuals from a three-generation family from southern Italy. This CPT1C mutation causes pure adult-onset spastic paraplegia. Moreover, CPT1C- deficient mice show corticospinal neurodegeneration with impaired motor function and muscle weakness. We are currently studying how CPT1C regulates the transport of organelles, such as endosomes or mitochondria, along the axon, and which molecular mechanisms are involved. We also give support to medical teams by performing the genetic diagnosis of HSP patients.