Blood markers could reveal oxidative stress in rare inherited amyloid disease
Researchers have identified plasma biomarkers that distinguish symptomatic from asymptomatic carriers of a rare inherited amyloidosis caused by TTR mutations. The findings suggest oxidative stress drives disease progression, opening potential avenues for earlier diagnosis and therapeutic intervention in a condition that currently has limited treatment options.
Originaltitel: Disrupted glutathione homeostasis in the pathogenesis of TTR-V30M amyloidosis.
Umeå universitet identifierar glutationhemostas som nyckelmekanisms i progressionen av TTR-V30M amyloidös. Forskargruppen mätte plasmanivåer av pyroglutamat, kynurenin och tryptofan hos friska kontroller, asymptomatiska bärare av mutationen och sjuka patienter. Symptomatiska individer uppvisade signifikant förhöjda pyroglutamatnivåer jämfört med båda kontrollgrupperna, vilket indikerar störd glutationhomostas. Parallellt var kynurenin/tryptofan-kvoten förhöjad bland sjuka bärare, vilket tyder på inflammatorisk aktivering. Resultaten kopplar oxidativ obalans direkt till sjukdomsmanifestation och öppnar vägen för nya terapeutiska ansatser. Strategier som återställer antioxidativ hemostas eller minskar inflammatorisk oxidativ stress kan potentiellt förskjuta sjukdomsupptakt eller sakta progression. För FoU-ledare inom farmaci utgör dessa biomarkörer möjlighet att utveckla och stratifiera behandlingar riktade mot redoxbalans.
BACKGROUND: Transthyretin (TTR) amyloidosis is a progressive, life-threatening disorder caused by extracellular deposition of amyloid fibrils derived from the plasma protein TTR. Inherited forms are associated with destabilizing TTR mutations; however, recent findings indicate that amyloid formation in vivo may be promoted by disulfide bond formation between TTR subunits, suggesting oxidative stress as a potential contributor to protein misfolding and disease progression. Glutathione (GSH) is a central component of the antioxidant defense system, and disruption of GSH homeostasis can lead to the accumulation of pyroglutamate (PGA), which is detectable in plasma. Moreover, oxidative stress is frequently linked to inflammation, which may be reflected by increased indoleamine 2,3-dioxygenase 1 (IDO1) activity, observed as an elevated plasma kynurenine/tryptophan ratio. METHODS: Plasma levels of PGA, kynurenine, and tryptophan were quantified by liquid chromatography-mass spectrometry in cohorts comprising healthy TTR wild-type controls, asymptomatic carriers of the TTR-V30M mutation, and symptomatic patients with TTR-V30M amyloidosis. RESULTS: Symptomatic individuals had significantly elevated plasma PGA levels compared with both asymptomatic carriers and age-matched healthy controls, consistent with impaired GSH homeostasis. In parallel, the kynurenine/tryptophan ratio was increased in symptomatic TTR-V30M carriers, supporting inflammatory activation in manifest disease. CONCLUSIONS: These findings identify disrupted GSH homeostasis and inflammatory activation as metabolic features associated with symptomatic TTR-V30M amyloidosis in vivo, supporting a link between redox imbalance and disease manifestation. Strategies aimed at restoring antioxidant homeostasis and limiting inflammatory oxidative stress may therefore warrant further investigation as approaches to delay onset or slow disease progression.