Involvement of Clusterin and the Aggresome in Abnormal Protein Deposits in Myofibrillar Myopathies and Inclusion Body Myositis

Abstract

Myofibrillar myopathies (MM) are characterized morphologically by the presence of non-hyaline structures corresponding to foci of dissolution of myofibrils, and hyaline lesions composed of aggregates of compacted and degraded myofibrillar elements. Inclusion body myositis (IBM) is characterized by the presence of rimmed vacuoles, eosinophilic inclusions in the cytoplasm, rare intranuclear inclusions, and by the accumulation of several abnormal proteins. Recent studies have demonstrated impaired proteasomal expression and activity in MM and IBM, thus accounting, in part, for the abnormal protein accumulation in these diseases. The present study examines other factors involved in protein aggregation in MM and IBM. Clusterin is a multiple-function protein which participates in Abeta-amyloid, PrP(res) and a-synuclein aggregation in Alzheimer disease, prionopathies and a-synucleinopathies, respectively. gamma-Tubulin is present in the centrosome and is an intracellular marker of the aggresome. Moderate or strong clusterin immunoreactivity has been found in association with abnormal protein deposits, as revealed by immunohistochemistry, single and double-labeling immunofluorescence and confocal microscopy, in MM and IBM, and in target structures in denervation atrophy. Gamma-Tubulin has also been observed in association with abnormal protein deposits in MM, IBM, and in target fibers in denervation atrophy. These morphological findings are accompanied by increased expression of clusterin and gamma-tubulin in muscle homogenates of MM and IBM cases, as revealed by gel electrophoresis and Western blots. Together, these observations demonstrate involvement of clusterin in protein aggregates, and increased expression of aggresome markers in association with abnormal protein inclusions in MM and IBM and in targets, as crucial events related to the pathogenesis of abnormal protein accumulation and degradation in these muscular diseases.

Pathophysiology of inflammatory and autoimmune myopathies

“…These proteins may accumulate in the cytoplasm of muscle fibers due to malfunctioning of the proteasome machinery, direct toxicity of monomers or oligomers of aberrant proteins and generation of cell stress, as described by Askanas et al [1][2][3]7]. Many of the noted accumulations however do not appear specific for IBM because they are also found in other vacuolar myopathies especially myofibrillar, hereditary IBM or even in chronic neurogenic conditions such as the postpolio syndrome [89][90][91][92][93][94][95][96]. Autophagic processing, which is relevant to degradation of intracellular proteins, may also play a role since the vacuoles have autophagic properties [97] involved in processing of APP/ b-amyloid.…”

Myofibrillar myopathies

“…1H), synemin, Xin, TAR DNA-binding protein 43 (TDP-43), and co-chaperones including αB-crystallin (Fig. 1E), heat shock protein (Hsp) 27 ( Fig.1I) and DNAJB2 [8][9][10][11][12][13][14][15][16]. Additional abnormal accumulation of several other proteins was documented in myotilinopathy and desminopathy.…”

Target Genes of Neuron-Restrictive Silencer Factor Are Abnormally Up-Regulated in Human Myotilinopathy

“…19,20 Preliminary work in our laboratory identified the presence of ubiquitin carboxy-terminal hydrolase L3 (UCHL3) in normal and diseased muscle, but UCHL1 was also present in the setting of abnormal protein deposits in MFMs. This was unexpected, because UCHL1 is abundant in brain and testis, whereas other members of the UCHL family, but not UCHL1, are expressed in other organs.…”