Novel Therapeutic Approaches for Inclusion Body Myositis

Thomas E. Lloyd


Curr Opin Rheumatol. 2010;22(6):658-664. 

In This Article

Is Inclusion Body Myositis a TDP-43 Proteinopathy?

The ubiquitinated aggregates and expanded autophagosomal vacuoles that are the pathological hallmarks of IBM suggest the possibility that a primary defect in autophagy leads to the accumulation of toxic macromolecular complexes or organelles. Many such protein aggregates have been identified in sIBM, as previously described (Aβ, phospho-tau, LC3, and p62 to name a few), suggesting that IBM may be caused by a generalized defect in protein degradation. Several recent studies have added a new member to this list, the RNA-binding protein TDP-43. TDP-43 is the major ubiquitinated aggregate-forming protein found in many neurodegenerative diseases, referred to as TDP-43 proteinopathies, including ALS and frontotemporal lobar degeneration (FTD) (reviewed in [58,59•]). Recently, several groups have identified TDP-43 protein aggregates in IBM muscle fibers, and these aggregates are not seen in polymyositis or dermatomyositis.[60,61,62••] Greenberg et al. report that sarcoplasmic TDP-43 aggregates are seen in 23% of fibers, much more frequently than amyloid or phospho-tau, seen in less than 3% of fibers in their study.[62••]

TDP-43 is normally nuclear, though it shuttles between the cytoplasm and nucleus. TDP-43 was initially discovered as a binding partner of the HIV-1 TAR terminal repeats, suggesting the intriguing possibility that the increased incidence of IBM in HIV patients may be related. In ALS and other TDP-43 proteinopathies, TDP-43 accumulates in the cytoplasm and is depleted from the nucleus. A central role of TDP-43 in the pathogenesis of ALS is suggested by the finding of autosomal dominant mutations in TDP-43 in familial ALS.[63,64] As in sporadic ALS, mutant TDP-43 is ubiquitinated and forms cytoplasmic aggregates, suggesting that cytoplasmic TDP-43 directly mediates toxicity. A central question in ALS and other TDP-43 proteinopathies is the mechanism of TDP-43-mediated toxicity.

A recent study[65•] suggests that TDP-43 is a major source of toxicity in IBMPFD. A genetic screen performed in a Drosophila model of IBMPFD identified the fly homolog of TDP-43 as a potent suppressor of VCP-mediated neurodegeneration. Epistasis experiments determined that TDP-43 toxicity functions downstream of VCP, suggesting that VCP-mediated degeneration is at least partially due to accumulation of TDP-43 in the cytoplasm. Importantly, clearance of TDP-43 accumulation in cell culture is accelerated with Rapamycin, suggesting that TDP-43 aggregates are removed by autophagy.[66•]


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