The Laboratory of Protein Chemistry
Director: Jorge Ghiso, Ph.D.

Biological systems have evolved specific mechanisms to ensure that proteins are immediately degraded if they fail to fold properly after synthesis. Despite these tightly regulated physiologic controls, several human diseases have been recently recognized to be associated with protein misfolding, aggregation and/or fibrillization. Among them, particular interest has been devoted to a large group of chronic and progressive neurodegenerative conditions characterized by selective loss of neurons associated either with cognitive, motor or sensory systems (e.g. Alzheimer’s, Prion diseases, Huntingtons, Parkinsons, ALS, etc.).

The Protein Chemistry Laboratory is focused in studying the molecular mechanisms involved in protein misfolding, with particular interest in those resulting in the formation of twisted fibrillar structures collectively known as amyloid. For reasons that are actively being investigated, under certain pathologic conditions several normal circulating proteins or their proteolytic degradation fragments deposit in the form of fibrils in different tissues, leading to cellular damage, organ dysfunction and eventually death. When fibrillar deposits occur in the central nervous system, they result in neurological disorders associated with cognitive deficits, dementia, stroke, cerebellar and extrapyramidal signs, or a combination thereof. The so-called sporadic cases constitute the vast majority of these disorders, although in many instances genetic abnormalities can be linked to a particular clinical and/or pathological hallmark.

Our research concentrates in deciphering the role of amyloid in the process of neurodegeneration. In Alzheimer's disease, the most frequent form of cerebral amyloidosis in humans and the most common type of dementia, amyloid (Aß) deposits co-localize with degenerating neurons in cognitive and associative areas of the brain. Interestingly, two hereditary conditions recently characterized in our laboratory, familial British dementia (FBD) and familial Danish dementia (FDD), are also associated with amyloid deposition in the central nervous system and neurodegeneration. Although the amyloid molecules identified in these disorders -ABri in FBD and ADan in FDD- are structurally unrelated to the Alzheimer's Aß peptide, neurofibrillary tangles containing the classical paired-helical filaments as well as neuritic components co-localize with the amyloid deposits in both diseases.

Moreover, the pattern of hyperphosphorylated tau immunoreactivity in FBD and FDD is almost indistinguishable from that observed in Alzheimer’s disease. Since these issues argue for the primary importance of the amyloid deposits in the mechanism(s) of neuronal cell loss, these disorders - FBD and FDD - may constitute alternative models to study the molecular basis of neurofibrillary degeneration, cell death and amyloid formation in the brain.

The study of rare diseases such as FBD or FDD, are likely to render key data for the better understanding of the basic molecular mechanisms responsible for the etiology and pathogenesis of fibrillar deposits in more common disorders (e.g. Alzheimer's disease).