α-Synuclein aggregation in the saliva of familial transthyretin amyloidosis: a potential biomarker.

Familial transthyretin amyloidosis (ATTR) is an autosomal dominant disease characterized by the formation of transthyretin (TTR) amyloid deposits. This crippling and fatal disease is associated with point mutations in TTR, a protein mainly produced in the liver. Hence, liver transplantation is the only treatment capable of halting disease progression. Ideally, liver transplantation should be performed as early as possible in the disease course before significant neurologic disability has been incurred. Early detection of disease before serious pathological lesions occur is crucial for the clinical management of patients and for morbidity delay. Unfortunately, the presence of TTR mutations by itself is not a predictor of disease onset or progression. In the present work, we observed an increased oligomerization of α-synuclein in the saliva of ATTR symptomatic individuals comparatively to asymptomatic carriers of the same TTR mutation and healthy control subjects. Based on this observation, we propose monitoring α-synuclein oligomers in saliva as a biomarker of ATTR progression. Since α-synuclein plays a major role in several neurodegenerative disorders, assessing its oligomerization state in this fluid provides a non-invasive approach to survey these pathologies.

A non-invasive method based on saliva to characterize transthyretin in familial amyloidotic polyneuropathy patients using FT-ICR high-resolution MS.

PURPOSE: To identify, characterize and perform a relative quantification of human transthyretin (TTR) variants in human saliva. EXPERIMENTAL DESIGN: Serum and saliva samples were collected from healthy and familial amyloidotic polyneuropathy (FAP) patients, proteins separated by SDS-PAGE, TTR bands excised, in-gel digested and analyzed by MALDI-FTICR. RESULTS: We identified and performed a relative quantification of mutated and native TTR forms in human saliva, based on FTICR-MS. The results are quantitatively identical to the ones obtained with human serum. In FAP patients subjected to cadaveric liver transplant, the TTR mutant form is no longer detected in saliva, while in patients receiving a domino liver from a FAP donor the mutant form of TTR becomes detectable in saliva, thus demonstrating the serum origin of TTR in saliva. CONCLUSIONS AND CLINICAL RELEVANCE: Saliva TTR originates in serum and the ratio of mutant to native TTR is preserved. The method provides a non-invasive detection of mutated TTR and a relative quantification of TTR forms. Diagnostic and disease prognosis of FAP is crucial at early stages of the disease and after liver transplantation, the only curative therapy. A suitable non-invasive method was developed for monitoring the most important FAP biomarker in human saliva.