Protein Aggregate Myopathies

Review Article Protein aggregate myopathies M. C. Sharma, H. H. Goebel1 All India Institute of Medical Sciences, New Delhi, India and 1Department of Neuropathology, Johannes Gutenberg University Medical Center, Mainz, Germany Protein aggregate myopathies (PAM) are an emerging group Aggegation of proteins within muscle cells may be of lyso- of muscle diseases characterized by structural abnormali- somal or nonlysosomal nature. The former occurs, for instance, ties. Protein aggregate myopathies are marked by the ag- in the neuronal ceroid-lipofuscinoses (NCL) as components gregation of intrinsic proteins within muscle fibers and fall of lipopigments, their accretion being a morphological hall- into four major groups or conditions: (1) desmin-related mark in the NCL.[1] This lysosomal accumulation of myopathies (DRM) that include desminopathies, a-B lipopigments renders the NCL a member of the lysosomal dis- crystallinopathies, selenoproteinopathies caused by muta- orders among which type-II glycogenosis, Niemann-Pick dis- tions in the, a-B crystallin and selenoprotein N1 genes, (2) ease, mucolipidosis IV and others may affect the skeletal hereditary inclusion body myopathies, several of which have muscle. been linked to different chromosomal gene loci, but with as Nonlysosomal accumulation of proteins within muscle fibers yet unidentified protein product, (3) actinopathies marked is a hallmark of a recently emerging subgroup of myopathies, by mutations in the sarcomeric ACTA1 gene, and (4) called protein aggregate myopathies (PAM). The cause of pro- myosinopathy marked by a mutation in the MYH-7 gene. tein accretion within muscle fibers – and other cell types of While PAM forms 1 and 2 are probably based on impaired other organs in the protein aggregate disorders – may be (a) extralysosomal protein degradation, resulting in the accu- impaired extralysosomal degradation of proteins, or (b) ab- mulation of numerous and diverse proteins (in familial types normal synthesis, (c) integration of proteins in the intracellu- in addition to respective mutant proteins), PAM forms 3 and lar structured constituents, e.g. sarcomeres. Proteins may 4 may represent anabolic or developmental defects because aggregate in soluble, granular and filamentous fashions. At of preservation of sarcomeres outside of the actin and myosin light microscopic level such protein aggregates can hardly be aggregates and dearth or absence of other proteins in these distinguished among the three different states of protein ag- actin or myosin aggregates, respectively. The pathogenetic gregation only the granular and filamentous aggregates may principles governing protein aggregation within muscle fibers be recognized by electron microscopy while aggregation of and subsequent structural sarcomeres are still largely un- known in both the putative catabolic and anabolic forms of soluble proteins may remain invisible and electron microscopic PAM. Presence of inclusions and their protein composition immunohistochemical labeling may not necessarily distinguish in other congenital myopathies such as reducing bodies, between a labeled soluble protein and an artificially misplaced cylindrical spirals, tubular aggregates and others await clari- label, (largely gold grains with or without silver enhancement) fication. The hitherto described PAMs were first identified The mutated proteins probably undergo faulty folding or by immunohistochemistry of proteins and subsequently by misfolding[2,3] and inappropriately expose their hydrophobic molecular analysis of their genes. surfaces for protein-protein interactions. In contrast to cor- rectly folded proteins, which are either soluble or associated Key words: actin; aggregation of proteins; congenital my- with cell membrane, these misfolded proteins are more insolu- opathies; desmin; inclusion body myopathies; myosin ble and result in aggregation. These aggregated proteins are less amenable to removal by molecular chaperones and the ubiquitin proteasome degradation pathway, which are the two main protective scavenging pathways of eurkaryotic cells against misfolded proteins. Protein aggregate myopathies may, therefore, belong to the emerging group of protein conforma- tional disorders. HH Goebel Department of Neuropathology, Johannes Gutenberg University Medical Center, Langenbeckstrasse 1, D-55101 Mainz, Germany E-mail: [email protected] Neurology India | September 2005 | Vol 53 | Issue 3 273 CMYK273 Sharma et al: Protein aggregate myopathies Protein aggregation in neuroectodermal cells has been known PAM. One of the trinucleotide repeat disorders, for a long time and is associated with certain diseases, largely oculopharyngeal muscular dystrophy, is also marked by in- of a neurodegenerative nature Like Alzheimer and prion dis- tranuclear accumulation of filaments representing the poly eases, Parkinson disease, multiple system atrophy, motor neu- (A)-binding protein 2. ron and Pick diseases, Alexander disease and a particular form Thus, the current group of PAM encompasses DRM, actin- of myoclonus epilepsy, called neuroserpinosis. Recent biochemi- related myopathies, myosin-related myopathies and a few oth- cal and molecular studies have not only further illustrated ers [Table 1]. protein aggregation, the biochemical components of the protein aggregates and the molecular background of many though PAM suggesting faulty protein degradation not all of them, but also have placed ‘protein aggregation’ as a The largest subgroup of myopathies falling into this cat- central pathogenetic issue in the forefront of research in egory are those marked by the accumulation of desmin and, neurodegenerative disorders. Intracellular protein aggrega- as a heterogeneous subgroup by itself, collectively also termed tion occurs in Alexander disease as Rosenthal fibers, second- ‘myofibrillar myopathy’.[4] This latter term refers to the ary due to mutations in the glial fibrillary acidic protein gene, myofibrillar lesions occurring when desmin accumulates within in neuroserpinosis as granular neuroserpin following muta- muscle fibers and, thus, emphasizes the sequelae to protein tions in the neuroserpin gene, and as Lewy bodies containing aggregation and disruption of sarcomeres. Clinically, DRM α-synuclein and neurofilaments, based on mutant α-synuclein are often of adult onset and, thereby, deviating from the expe- in one of the familial types of Parkinson disease. Alzheimer rience in other CM, which usually commence in childhood. disease, however, shows intracellular accumulation of proteins Further distinctive features are the distribution of muscle as paired helical filaments rich in tau and extracellular accu- weakness, with generalized or proximal weakness prevailing mulation of aggregates of fibrils called amyloid. Extracellular in childhood CM but often distal in DRM, and cardiac symp- fibrillar protein aggregation of amyloid also occurs in prion toms, occasionally even resulting in sudden death in DRM. diseases owing to the extracellular deposition of abnormal prion This latter feature of cardiac involvement is not surprising as proteins. Whether intracellular aggregation of proteins, which abnormalities of desmin, the muscle cell-specific intermediate are often hyperphosphorylated, follow pathogenetic principles filament protein affects skeletal muscle fibers, cardiac similar or identical to those of extracellular protein aggrega- myocytes and smooth muscle cells, i.e. in man by aggregation tion has not completely been clarified. Extracellular protein of desmin, in the desmin knock-out mouse by severe necrotiz- aggregation, apart from formation of AL-amyloid as a fea- ing lesions in the cells and respective organs such as skeletal ture of generalized amyloidosis owing to formation of abnor- muscle, heart and major arteries. Desmin forms an intricate mal immunoglobulins in plasma cell dyscrasias and plasma- intracellular network or cytoskeleton, linking nuclei via sar- cytoma, has not been seen in any of the myopathies marked comeric Z-bands to the plasma-sarcolemma. In PAM not only by intracellular protein aggregation. Pathogenesis and mor- protein aggegation occurs as a conspicuous morphological phogenesis in protein aggregation within muscle fibers are hallmark but, most likely, also causes disruption of this inter- still incompletely understood. The frequent occurrence of pro- mediate filament network and, thereby, its function. tein aggregation in genetic myopathies, which is responsible Morphologically, DRM may be grouped into two types, those for the formation of mutant poteins, suggests that respective marked by inclusion bodies and those marked by accumula- mutant proteins play a crucial role in protein aggregation, tion of granulofilamentous material, although both features perhaps acting as seeds for the assembly of other nonmutant proteins as well. Table 1: Protein aggregate myopathies Among sarcomeric and sarcomere-related proteins, numer- DRM Desminopathies ous proteins are associated with certain myopathies, which α-B Crystallinopathy largely belong to the group of congenital myopathies (CM). Selenoproteinopathies Nemaline myopathies are found genetically heterogeneous, 2q21 Myopathy and others involving mutations in genes for nebulin, actin, troponin-T 10q23 Myopathy 15q22 CRD myopathy and tropomyosins 2 and 3, of which, however, only actin may accumulate in respective patients with the mutational ACTA Actinopathies 1 type of nemaline myopathy. Although α-actinin is a major ARM Myosin-storage

Load more