Surface exposed epitopes and structural heterogeneity of in vivo formed transthyretin amyloid fibrils

Transthyretin (TTR) is a tetrameric protein that can dissociate into amyloidogenic monomers and cause TTR-related amyloidosis. A rare phenotype, called hereditary leptomeningeal TTR amyloidosis, in which TTR amyloid deposition occurs mainly in leptomeninges and subarachnoid vessels, has been reported in patients with several different TTR variants. In the present study, we examined TTR variants immunoprecipitated from the serum and cerebrospinal fluid (CSF) of patients with hereditary leptomeningeal TTR amyloidosis using matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (IP-Mass method). The leptomeningeal-type TTR variants were not detected in the serum but were found at low levels in the CSF. The undetectable levels of the leptomeningeal-type TTR variants in serum could explain the minute amounts of systemic deposition of these variants. The relatively high level of unstable TTR variants in CSF, probably due to increased secretion from the choroid plexus, is considered to be the pathogenesis of the leptomeningeal-type of TTR amyloidosis.

Biochemical characteristics of variant transthyretins causing hereditary leptomeningeal amyloidosis

Unusual self-association properties of transthyretin Y114C related to familial amyloidotic polyneuropathy: Effects on detection and quantification

Many proteins can undergo pathological conformational changes that result in the formation of amyloidogenic fibril structures. Various neurodegenerative diseases are associated with such pathological fibril formation of specific proteins. Transthyretin (TTR) is a tetrameric globular transport protein in the blood plasma that can dissociate, unfold, and form long and stable fibrils. Many TTR mutations are known that promote (TTR) amyloidosis and cause severe diseases. TTR amyloidosis has been studied extensively using biochemical methods and structures of various mutations in the globular form have been characterized. Recently, also the structure of a TTR fibril has been determined. In an effort to better understand why some mutations increase or decrease the tendency of amyloid formation, we have applied a combined molecular dynamics and continuum solvent approach to calculate the energetic influence of residue changes in the globular versus fibril form. For 29 out of 36 tested TTR single residue mutations, the approach correctly predicts the increased or decreased tendency for amyloidosis allowing us also to elucidate the origins of the tendency. We find that indeed the destabilization of the globular monomer or changes in dimer and tetramer stability due to mutation has a dominant influence on the amyloidogenic tendency. The continuum solvent model predicts a significantly more favorable mean energy per residue of the fibril form compared to the globular form. This effect is only slightly modulated by single‐point mutations preserving the energetic preference for fibril formation upon protein unfolding. It explains why no correlation between experimental amyloidosis and calculated change in fibril stability was observed.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/prot.26399

Analysis of amyloidogenic transthyretin mutations using continuum solvent free energy calculations

Objective: To clarify the pathogenesis of leptomeningeal amyloidosis in familial amyloidotic polyneuropathy amyloidogenic transthyretin Y114C (FAP ATTR Y114C). Methods: The authors analyzed eight FAP ATTR Y114C patients. Six patients showed CNS symptoms associated with leptomeningeal amyloidosis. To examine the function of the blood–CSF barrier and blood–brain barrier (BBB), the authors performed CSF and MRI studies. The authors also performed a histopathologic study of autopsy specimens to examine the distribution of amyloid deposition in the CNS. Results: CSF study showed high total protein concentrations and increased albumin CSF/serum concentration quotients (Q alb ; an indication of blood–CSF barrier function). MRI with gadolinium (Gd) revealed enhancement from brainstem to spinal cord. Serial brain MRI studies with FLAIR images after Gd administration showed Gd leakage into the subarachnoid space (two patients). These findings suggested the blood–CSF barrier and BBB dysfunctions. Constructive interference in steady state (CISS) three-dimensional Fourier transformation (CISS-3DFT) sequence analysis demonstrated amyloid-induced funiculus structures joining the spinal cord and dura mater (one patient). Histopathologic study revealed intense amyloid deposition in leptomeninges, vessel walls, and parenchyma in spinal cord and the brain. These distributions of amyloid deposition are unique compared to other TTR related leptomeningeal amyloidosis. Conclusions: Patients with familial amyloidotic polyneuropathy amyloidogenic transthyretin Y114C had CNS disorders related to amyloid deposition in leptomeninges, vessel walls, and parenchyma in spinal cord and the brain. The pathogenesis of CNS disorders may reflect disruption of the blood–CSF barrier and blood–brain barrier by amyloid deposition.

Neuroradiologic and clinicopathologic features of oculoleptomeningeal type amyloidosis

A Dutch kindred with transthyretin Cys 114 related familial amyloidotic polyneuropathy is reported. The jnding of early involvement of the heart is of great concern and of special relevance to the optimal timing for liver transplantation. to date, the variant had only been reported to be present in Japan. The variant was identlfied by PCR DNA ampllfication, single strand conformation polymorphism analysis and DNA sequence analysis. Total transthyretin serum levels in 6 Cys 114 patients (median 115 mg/l, range 70-150) were found to be significantly lower than in 12 Met 30 patients (median 325 mg/l, range 160-590) (p<0.0001), which suggests rapid breakdown andor transformation into amyloid andor decreased synthesis.

A Dutch kindred with familial amyloidotic polyneuropathy associated with the transthyretin Cys 114 mutant

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A Dutch kindred with familial amyloidotic polyneuropathy associated with the transthyretin Cys 114 mutant