Keratinic amyloid deposition in canine hair follicle tumors

Abstract

Keratinic primary localized cutaneous amyloidosis is a disease in humans; however, no similar condition has been reported in animals. This study aimed to investigate cutaneous keratinic amyloid deposition in dogs and elucidate its etiology. Canine hair follicle tumor tissues were histopathologically analyzed. Immunohistochemistry and mass spectrometry–based proteomic analyses were performed to identify precursor protein candidates. Structural prediction and in vitro fibrillization analyses were conducted to determine the amyloidogenic region and gene sequencing analysis was performed to assess mutations. Of the 266 samples, 16 had amyloid deposition. Amyloid deposits were found in the stroma of tumors and in the margins of keratin debris and around normal hair follicles. Cytokeratin 5 (CK5) was identified as a precursor protein candidate. C-terminal truncation of CK5 was observed in amyloid deposits, and the truncation sites varied depending on the deposition pattern. There was a significantly higher incidence of amyloid deposition in Shiba dogs, and CK5 amino acid polymorphisms were identified in these dogs. A part of the C-terminal region of both canine and human CK5 exhibited highly amyloidogenic properties in vitro. This study revealed the existence of cutaneous keratinic amyloid deposition in animals and identified CK5 as an amyloid precursor protein, providing novel insights into understanding the etiology of cutaneous amyloidosis.

Identification of apolipoprotein E-derived amyloid within cholesterol granulomas of leopard geckos (Eublepharis macularius)

“…Serum amyloid P-component, histone, and vitronectin, which have been reported as amyloid signature proteins in humans and some animal species 1 , 21 , 22 , 28 , were detected at low levels in some samples, proving the presence of amyloid fibrils in the microdissected samples. Keratin 5, previously reported as an amyloid precursor protein in dogs 4 , was detected in animals 4 and 5, but at much lower levels than ApoE. The number of ApoE-derived peptides detected in animals 4–8 by mass spectrometry was mapped schematically to identify the amyloidogenic regions of ApoE (Fig.…”

“…To diagnose ApoAIV amyloidosis, it is necessary that ApoAIV be detected at high levels, and that other amyloid precursor proteins be absent on proteomic analysis 9 , 32 . This study detected ApoE at very high scores in all animals, and other amyloidogenic proteins, including keratin 5 detected at low levels, were excluded 4 . Therefore, we concluded that ApoE is not an amyloid signature protein but an amyloid precursor protein within cholesterol granulomas of leopard geckos.…”

“…These results indicate that ApoE-derived amyloid was deposited within cholesterol granulomas of leopard geckos. ApoE has been known to be co-deposited with amyloid fibrils as an amyloid signature protein in human and animal amyloidosis 1,[3][4][5][6][7]21,22 . To date, whereas the amyloidogenicity of ApoE has not been demonstrated in vivo, various apolipoproteins such as serum amyloid A, ApoAI, apolipoprotein A-II, ApoAIV, apolipoprotein C-II, and apolipoprotein C-III (ApoCIII) have been identified as amyloid precursor proteins in humans and/or animals 2,5,8,9,29-32 .…”

“…Amyloidosis is a protein misfolding disease characterized by amyloid fibril deposition in tissues and classified by amyloid precursor proteins and deposited sites 1,2 . To date, 42 types of amyloidosis have been identified in humans and nearly 20 types in animals 1,[3][4][5][6][7][8][9] . Notably, some amyloid precursor proteins in animals, such as α-S2 casein and lipopolysaccharide-binding protein, have not been proven to have in vivo amyloidogenicity in humans 7,10 .…”

Identification of Ameloblastin as an Amyloid Precursor Protein of Amyloid-Producing Ameloblastoma in Dogs and Cats

“…These results clearly support that the N-terminal region of ameloblastin is involved in amyloid formation. In various types of amyloidosis, protein destabilization associated with proteolysis plays an important role in misfolding and subsequent amyloid formation [ 30 ]. Further, also in APAB, it is possible that the N-terminal region of ameloblastin is degraded by some mechanism, resulting in the formation of amyloid.…”