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Alan Solomon

Publications and source records attributed to Alan Solomon.

26 records · Page 2Linked to original sources
PubMed2003

Calcifying epithelial odontogenic (Pindborg) tumor-associated amyloid consists of a novel human protein.

Calcifying epithelial odontogenic tumors (CEOTs), also known as Pindborg tumors, are characterized by the presence of squamous-cell proliferation, calcification, and, notably, amyloid deposits. On the basis of immunohistochemical analyses, the amyloidogenic component had heretofore been deemed to consist of cytokeratin-related or other molecules; however, its chemical composition had never been elucidated. We have used our microanalytic techniques to characterize the protein nature of CEOT-associated amyloid isolated from specimens obtained from 3 patients. As evidenced by the results of amino-acid sequencing and mass spectrometry, the fibrils were found to be composed of a polypeptide of approximately 46 mer. This component was identical in sequence to the N-terminal portion of a hypothetical 153-residue protein encoded by the FLJ20513 gene cloned from the human KATO III cell line. That the amyloid protein was derived from this larger molecule was demonstrated by reverse transcription-polymerase chain reaction amplification of tumor-cell RNA where a full-length FLJ20513 transcript was found. Furthermore, immunohistochemical analyses revealed that the amyloid within the CEOTs immunostained with antibodies prepared against a synthetic FLJ20513-related dodecapeptide. Our studies provide unequivocal evidence that CEOT-associated amyloid consists of a unique and previously undescribed protein that we provisionally designate APin.

Adolescent↗
PubMed2003

Immunotherapy in systemic primary (AL) amyloidosis using amyloid-reactive monoclonal antibodies.

Heretofore, treatment of patients with primary or light chain-associated (AL) amyloidosis has been directed toward reducing the synthesis of the amyloidogenic precursor protein through conventional or high-dose cytotoxic antiplasma cell chemotherapy. Although such efforts have extended survival, most often the prognosis remains exceedingly poor due to the persistence (or progression) of the pathologic deposits. The development of murine amyloid-reactive monoclonal antibodies (mAbs) has provided another therapeutic approach; namely, passive immunotherapy. These reagents, prepared against human light chain-related fibrils, recognize an epitope common to the beta-pleated structure of AL and other types of amyloid proteins and can effect rapid amyloidolysis when administered to mice injected with human AL amyloid extracts. One such prototypic antibody, the IgG1kappa mAb 11-1F4, has now been chimerized and is undergoing GMP production for an eventual phase I and II clinical trial in patients with AL amyloidosis. Demonstration of the therapeutic efficacy of this amyloid-reactive mAb would provide an important proof-of-principle that this form of immunotherapy also could benefit individuals with other types of inherited or acquired amyloid-associated disease.

Amyloid↗
PubMed2003

A model for amyloid fibril formation in immunoglobulin light chains based on comparison of amyloidogenic and benign proteins and specific antibody binding.

In an attempt to understand the mechanism of amyloid fibril formation in light chain amyloidosis, the properties of amyloidogenic (SMA) and benign (LEN) immunoglobulin light chain variable domains (VL) were compared. The conformations of LEN and SMA were measured using secondary and tertiary structural probes over the pH range from 2 and 8. At all pH values, LEN was more stable than SMA. The CD spectra of LEN at pH 2 were comparable to those of SMA at pH 7.5, indicating that the low pH conformation of LEN closely resembles that of SMA at physiological pH. At low pH, a relatively unfolded intermediate conformation is populated for SMA and rapidly leads to amyloid fibrils. The lack of such an intermediate with LEN, is attributed to sequence differences and accounts for the lack of LEN fibrils in the absence of agitation. A kappa IV-specific monoclonal antibody that recognizes the N-terminal of SMA caused unraveling of the fibrils to the protofilaments and was observed to bind to one end of SMA protofilaments by atomic force microscopy. The antibody result indicates that each protofilament is asymmetric with different ends. A model for the formation of fibrils by SMA is proposed.

Amyloid↗
PubMed2003

Hepatic amyloidosis resulting from deposition of the apolipoprotein A-I variant Leu75Pro.

Apolipoprotein A-I amyloidosis (AApo A-I) is an inherited systemic disease that results from pathologic deposition in tissues of fibrils composed of Apo A-I-related molecules. This disorder has been linked to mutations occurring within the coding region of the Apo A-I gene and heretofore, nine such variants had been described. Recently, a tenth alteration was found in an Italian population where the substitution of proline for leucine at position 75 (Leu75Pro) was associated with amyloid deposits in the liver. We now report our studies on a patient of different ethnicity who has hepatic amyloidosis and a similar mutation in the amyloidogenic precursor protein, as evidenced from analyses of genomic Apo A-I-encoding DNA. Additionally, fibrils extracted from the liver and characterized chemically were found to be composed almost exclusively of a approximately 96 residue N-terminal Apo A-I fragment that contained the Leu75Pro substitution. RFLP analyses revealed that the patient was heterozygous for this mutation; however, < 10% of the plasma Apo A-I consisted of the aberrant protein while the remainder had the normal (wild-type) sequence. Our findings provide further evidence that the Leu75Pro variant is associated with a predominant hepatic phenotype and can occur in individuals of diverse ethnic backgrounds.

Amino Acid Sequence↗
PubMed2003

Transthyretin-derived senile systemic amyloidosis: clinicopathologic and structural considerations.

Senile systemic amyloidosis (SSA) is a prevalent disease affecting the elderly and results from the pathologic deposition, predominantly in the heart, of unmutated (wild-type) transthyretin (TTR) molecules. This disorder differs from the familial TTR-associated amyloidoses that generally occur in a younger population and involves peripheral nerves but, notably, the deposits contain mutated (variant) forms of the amyloidogenic precursor protein. To gain further insight into the clinicopathologic features and pathogenesis of SSA, we have reviewed the post-mortem findings of 33 Swedish individuals (27 men, 6 women) who had pronounced cardiac amyloid disease. Additionally, in all cases there were amyloid deposits within the lungs. Seven of the patients were uremic, possibly due to fibrillar deposits in the renal medullary papilla. In contrast to other systemic amyloidoses, none of the 33 had more than minute congophilic material in the renal cortex, liver, or spleen. We have also analyzed the chemical composition of fibrils extracted from myocardium and have found that the protein consisted mainly of C-terminal fragments of TTR starting at positions 46, 49, and 52. Furthermore, we identified through antigenic mapping, an epitope present on the H strand of fibrillar, but not normal, plasma TTR molecules indicating that this strand is exposed in fibrils. We suggest that ATTR fibrils may develop both from full-length TTR and from C-terminal TTR fragments and that the N-terminal part is not necessary for the fibril integrity.

Aged↗
PubMed2002

Transmissibility of systemic amyloidosis by a prion-like mechanism.

The generation of amyloid fibrils from an amyloidogenic polypeptide occurs by a nucleation-dependent process initiated in vitro by seeding the protein solution with preformed fibrils. This phenomenon is evidenced in vivo by the fact that amyloid protein A (AA) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an i.v. injection of protein extracted from AA amyloid-laden mouse tissue. Heretofore, the chemical nature of this "amyloid enhancing factor" (AEF) has not been definitively identified. Here we report that the active principle of AEF extracted from the spleen of mice with silver nitrate-induced AA amyloidosis was identified unequivocally as the AA fibril itself. Further, we demonstrated that this material was extremely potent, being active in doses <1 ng, and that it retained its biologic activity over a considerable length of time. Notably, the AEF was also effective when administered orally. Our studies have provided evidence that AA and perhaps other forms of amyloidosis are transmissible diseases, akin to the prion-associated disorders.

Administration, Oral↗
PubMedDate not supplied

Structural basis of light chain amyloidogenicity: comparison of the thermodynamic properties, fibrillogenic potential and tertiary structural features of four Vlambda6 proteins.

Primary (AL) amyloidosis results from the pathologic deposition of monoclonal light chains as amyloid fibrils. Studies of recombinant-derived variable region (VL) fragments of these proteins have shown an inverse relationship between thermodynamic stability and fibrillogenic potential. Further, ionic interactions within the VL domain were predicted to influence the kinetics of light chain fibrillogenicity, as evidenced from our analyses of a relatively stable Vlambda6 protein (Jto) with a long range electrostatic interaction between Asp and Arg side chains at position 29 and 68, respectively, and an unstable, highly fibrillogenic Vlambda6 protein (Wil) that had neutral amino acids at these locations. To test this hypothesis, we have generated two Jto-related mutants designed to disrupt the interaction between Asp 29 and Arg 68 (JtoD29A and JtoR68S). Although the thermodynamic stabilities of unfolding for these two molecules were identical, they exhibited very different kinetics of fibril formation: the rate of JtoD29A fibrillogenesis was slow and comparable to the parent molecule, whereas that of JtoR68S was significantly faster. High-resolution X-ray diffraction analyses of crystals prepared from the two mutants having the same space group and unit cell dimensions revealed no significant main-chain conformational changes. However, several notable side-chain alterations were observed in JtoR68S, as compared with JtoD29A, that resulted in the solvent exposure of a greater hydrophobic surface and modifications in the electrostatic potential surface. We posit that these differences contributed to the enhanced fibrillogenic potential of the Arg 68 mutant, since both Jto mutants lacked the intrachain ionic interaction and were equivalently unstable. The information gleaned from our studies has provided insight into structural parameters that in addition to overall thermodynamic stability, contribute to the fibril forming propensity of immunoglobulin light chains.

Amino Acid Sequence↗