Prion diseases, also known as transmissible spongiform encephalopathies, are progressive and invariably fatal degenerative disorders of the central nervous system that affect humans and other mammals. They result from the structural change of a cellular protein, denominated PrP, into an abnormal form, known as prion, that propagates in the brain of the patients by inducing conversion of native PrP. The prion can be transmitted between different species. This was the case for ‘mad cow’ disease which was transmitted to humans causing a variant form of Creutzfeldt-Jakob disease.
Our research focuses on defining the mechanisms of neurodegeneration and devisingt herapeutic approaches for prion diseases. We are also interested in the mechanism linking the spread of abnormal proteins and neurotoxicity in other neurodegenerative conditions.
Mechanisms of neurodegeneration in genetic prion diseases
Genetic prion diseases are caused by mutations in the gene encoding PrP. Different mutations are associated with different clinical manifestations, ranging from cognitive and motor deficits to sleep alterations, autonomic dysfunction and psychiatric disorders. How mutant PrP causes neuronal dysfunction leading to different diseases is not known. We have developed a research program to tackle this question, using transfected cells, transgenic mice and primary neuronal cultures.
Development of anti-prion molecules
We have developed a research program to identify small molecules that down-regulate PrP and/or prevent its conformational change. The potential therapeutic activity of the identified compounds is tested in cell and mouse models of genetic and acquired prion diseases.
Prion-like protein spreading in neurodegenerative diseases
There is evidence that several aggregated proteins such as amyloid-beta in Alzheimer's disease, tau in the tauopathies, and alpha-synuclein in Parkinson disease, are able to spread in a prion-like manner in the central nervous system. We are investigating the mechanism linking spread of abnormal proteins and neurodegeneration in these diseases. We have demonstrated that traumatic brain injury induces a prion form of the protein tau that can spread through the brain, resulting in memory deficits and neuronal damage.
Mechanism of neurodegeneration in Marinesco-Sjögren syndrome
Marinesco-Sjögren syndrome (MSS) is a rare genetic disease of early infancy linked to mutations in the SIL1 gene, causing cerebellar atrophy, degeneration of skeletal muscle and cataracts. SIL1 is important for the correct folding and intracellular transport of proteins. SIL1 deficiency leads to the accumulation of misfolded proteins in the cell and activation of stress responses similar to those seen in prion diseases. We are studying the mechanisms responsible for cerebellar degeneration, and testing potential therapies in cell and mouse models.
International Consensus on Cardiopulmonary Resuscitation.