Protein Aggregates and Aggrephagy in Myopathies

Abstract

A number of muscular disorders are hallmarked by the aggregation of misfolded proteins within muscle fibers. A specialized form of macroautophagy, termed aggrephagy, is designated to remove and degrade protein aggregates. This review aims to summarize what has been studied so far about the direct involvement of aggrephagy and the activation of the key players, among others, p62, NBR1, Alfy, Tollip, Optineurin, TAX1BP1 and CCT2 in muscular diseases. In the first part of the review, we describe the aggrephagy pathway with the involved proteins; then, we illustrate the muscular disorder histologically characterized by protein aggregates, highlighting the role of aggrephagy pathway abnormalities in these muscular disorders.

Keywords: aggrephagy; aggresome; muscle disorders; protein aggregates; protein quality control (PQC).

Figure 1

Schematic representation of the known aggrephagy modulators. Misfolded ubiquitinated proteins are recognized by the selective aggrephagy receptors such as p62 and NBR1 which jointly associate through their UBA domains to the ubiquitins that tag misfolded proteins. Moreover, via their LIR domains they interact with LC3. Tollip, optineurin and TAX1BP1 can also recognize ubiquitinated aggregates, with TAX1BP1 being mobilized to the aggregates by NBR1. The large protein Alfy can act as a scaffold, stabilizing the forming phagophore and interacting with LC3 and p62. HDAC6 is also facilitating the selective aggregates’ removal by bridging the ubiquitinated proteins to the microtubule motor dynein, which can guide the aggregates toward the microtubule organization centre (MTOC) where aggresomes are localized. Furthermore, HDAC6 recruits and de-acetylates cortactin which, once activated, can assemble an F-actin network surrounding aggregates and lysosome, thus facilitating the fusion between lysosome and utophagosome. Likewise, CCT2 in its monomeric form can recognize aggregated proteins independent of ubiquitin-binding receptors and direct them towards the nascent autophagosome through interaction with LC3 via its VLIR motif. (Figure created with Biorender.com, Toronto, ON, Canada).

Figure 2

Histology from muscle biopsies of patients affected by muscle diseases with aggrephagy involvement. (a) hematoxylin/eosin (H&E) staining of a muscle biopsy from a patient affected by a mutation in the myotilin gene highlighting fiber size variability, intracitoplasmatic and subsarcolemmal eosinophilic areas (*), vacuoles, either rimmed or not (arrows); (b) H&E of a muscle biopsy from a patient with a mutation in the desmin gene showing fiber size variability, with concomitant atrophy and hypertrophy, some fibers present basophilic and granular cytoplasmic material (*) and vacuoles (arrows); (c,d) histological findings in a muscle biopsy of an sIBM patient, showing atrophic and hypertrophic muscle fibers, with scattered and groups of small angulated fibers, fiber with rimmed vacuoles and vacuoles with a rim of granular basophilia in H&E (c), that is stained in red with Gomori trichrome (d); (e) muscle biopsy from a patient affected by OPMD, demonstrating variability in fibers size, rare internal nuclei, scattered atrophic and hypotrophic fibers and rimmed vacuoles (arrows); (f) muscle biopsy from a patient affected by PLIN4-related myopathy demonstrating numerous degenerated fibers, frequent central nuclei, fibers splitting and vacuoles (arrow).