Spastic paraplegia

The hereditary spastic paraplegias (HSP's) comprise a heterogeneous group of upper motor neuron diseases. More than 25 disease loci have been mapped and mutations in 11 genes have been identified to date. HSP is characterised by progressive lower-limb weakness, spasticity and subtle impairment of the vibratory sense. The age of onset of the disease is quite variable, generally lying between 10 and 40 years. Degeneration of the lateral corticospinal tracts is a typical pathological presentation of HSP which increases in severity caudally.

Hypotheses

Good experimental evidence has recently emerged to support two main hypotheses for the neurodegeneration seen in HSP, as well as some other neurodegenerative conditions: abnormal mitochondrial function, and defective subcellular transportation mechanics. A specific mitochondrial malfunction seems to affect neuronal metabolism, in particular at the axon ends, by reducing the available energy. The cellular trafficking impairment would limit the turnover of fresh molecules and organelles to and from the periphery of neurons. Both mechanisms would result in a dying-back effect, typical of this late-onset progressive neurodegeneration.

Aims of the project

We plan to investigate these hypotheses by developing and analysing a set of cellular and animal models of HSP. The workplan includes the development of seven novel animal models beside the further characterisation of the paraplegin null mutant already generated, the functional characterisation of the HSP mitochondrial dysfunction and impaired mitochondrial protein quality control, and the relationship between defective trafficking dynamics and axonal degeneration.