Neuromuscular Pathology in Hereditary Gelsolin Amyloidosis

Abstract

Hereditary gelsolin amyloidosis (AGel amyloidosis) is a systemic disorder reported worldwide in kindreds with a G654A or G654T gelsolin gene mutation. The clinically characteristic peripheral nerve involvement has been poorly characterized morphologically, and its pathogenesis remains unknown. We studied peripheral nerve and skeletal muscle biopsy or autopsy specimens of 35 patients with a G654A gelsolin gene mutation. Histological, immunohistochemical, and electron microscopic studies showed consistent deposition of gelsolin amyloid (AGel), particularly in the vascular walls and perineurial sheaths. Nerve roots were more severely affected than distal nerves. The amyloid deposits also displayed variable immunoreactivity for apolipoprotein E, amyloid P component, cystatin C, and alpha-smooth muscle actin. Sural nerve morphometry showed preferential age-related large myelinated nerve fiber loss and reduction of myelin sheath cross-sectional area. There was evidence of denervation atrophy and fiber type grouping in skeletal muscle. Our study shows that marked proximal nerve involvement with AGel angiopathy is an essential feature of AGel amyloidosis. The preferential large fiber loss, not generally seen in amyloid neuropathy, may be caused by ischemia due to AGel angiopathy. Deficient actin modulation by variant gelsolin in neurons and Schwann cells, however, may alter axonal transport and myelination and contribute to AGel polyneuropathy.

Secretion of amyloidogenic gelsolin progressively compromises protein homeostasis leading to the intracellular aggregation of proteins

“…It may be that analysis of much older (Ϫ/ϩ) mice will reveal a muscle weakness pheno- type. The muscular weakness observed in the homozygous D187N (ϩ/ϩ) gelsolin mice is consistent with the clinical findings in both sIBM and FAF patients (18,19).…”

“…Only a fraction of D187N/Y plasma gelsolin in FAF is cleaved by furin; the remainder is secreted as full-length, functional plasma gelsolin. C68 can be further cleaved in the extracellular space by a type I matrix metalloprotease, like MT1-MMP (12), to generate the major (8-kDa) and minor (5-kDa) amyloidogenic fragments that deposit in blood vessel walls, skin, the autonomic nervous system, and the eye of humans, causing cranial and peripheral polyneuropathy, cutis laxa, and corneal lattice dystrophy (18). Deposition also occurs in skeletal and cardiac muscle, leading to cardiomyopathy and muscle weakness (14,18).…”

“…C68 can be further cleaved in the extracellular space by a type I matrix metalloprotease, like MT1-MMP (12), to generate the major (8-kDa) and minor (5-kDa) amyloidogenic fragments that deposit in blood vessel walls, skin, the autonomic nervous system, and the eye of humans, causing cranial and peripheral polyneuropathy, cutis laxa, and corneal lattice dystrophy (18). Deposition also occurs in skeletal and cardiac muscle, leading to cardiomyopathy and muscle weakness (14,18). Given that human D187N/Y plasma gelsolin is expressed in most tissues and that the C68 fragment is in the blood, the origin of the amyloidogenic fragments (local production versus serumderived) has been unclear, as are the events contributing to age-onset proteotoxicity.…”

Amyloidogenesis of Natively Unfolded Proteins

“…Extensive deposition of mutant gelsolin fragments as amyloid in the basement membrane of the skin, blood vessel walls, central nervous system, and the ocular system causes cutis laxa, cranial neuropathy, and corneal lattice dystrophy [316][317][318]. The mutations (D187N/Y) causing gelsolin amyloidosis disrupts Ca 2+ binding within domain 2 which makes it susceptible to aberrant cleavage by furin yielding a secreted 68 kDa fragment referred to as C68 [319,320].…”

Membrane Initiated Gelsolin Amyloid Formation

“…This causes replacement of an aspartate residue Asp 187 with asparagine or tyrosine, which makes gelsolin susceptible to aberrant trypsin-like protease cleavage site between residues Arg 172 -Ala 173 (Kangas et al, 1996). Structural changes unmask an aberrant proteolysis site at Arg 172 -Ala 173 leading to a trypsin-protease sensitive molecule (Kiuru, 1998, Kiuru et al 1999Kiuru-Enari et al, 2002). The hydrolysis at the Arg 172 -Ala 173 site results in the formation of a 68 kDa C-terminal fragment, which is further digested at the Met 243 residue, forming an amyloidogenic 8.1 kDa peptide containing residues 173-243 (G173-243) of gelsolin domain S2 (Maury et al, 1997(Maury et al, , 1994 , spontaneously associate into amyloid fibrils.…”