Molecular links in hereditary spastic paraplegia European research on a rare but highly debilitating condition, hereditary spastic paraplegia (HSP), has uncovered valuable information on the proteins implicated in the development of this disease. Health © Thinkstock HSP is a neurodegenerative disorder that results in progressive weakness and spasticity of the lower limbs. The condition manifests itself as 'pure' where there are no other symptoms or 'complicated' when associated with other neurological abnormalities such as dementia and deafness. The 'Genetic models of chronic neuronal degeneration causing hereditary spastic paraplegia' (Spasticmodels) project investigated elements of two main hypotheses to explain neurodegeneration in HSP. The first possibility is based on the power house of the cell, the mitochondrion therefore affecting neuronal metabolism, particularly at the axon which takes information away from the cell body. The other possibility, defective sub-cellular transport mechanics, would limit the fresh turnover of molecules and organelles to the periphery of nerve cells. Project scientists, with the aid of seven specially designed novel mouse models and a null model, tested the importance of genes and proteins. For parameters of neuronal dysfunction, different mouse phenotypes were characterised for behavioural, neuropathological and biochemistry markers. For mitochondrial function, proteins researched included paraplegin, the m-AAA complex and heat shock protein (HSP)60. Proteins implicated in axonal trafficking, kinesin, spastin and spartin, were also investigated. Furthermore, the relationship between defective trafficking dynamics and degeneration of the axons came under scrutiny. Dissemination to key stakeholders being crucial, Spasticmodels have direct connections to all-important patient associations including the Tom-Wahlig-Stiftung and the Italian Telethon Foundation. Information available on Spasticmodels' progress will be in a format suitable for a wide audience. A separate report for consortium members is available and can be used to disseminate material to the press and other media. Spasticmmodels' highly integrated approach has shed light on several HSP genes identifying common mechanisms leading to axonal degeneration. Long term, these will be potential targets for therapeutic interventions.
