Valosin Containing Protein Associated Fronto-Temporal Lobar Degeneration:Clinical Presentation, Pathologic Features and Pathogenesis

C.      C. Weihl

Abstract

Inclusion body myopathy (IBM) associated with pagets disease of the bone (PDB) and fronto-temporal dementia (FTD) or IBMPFD, is a rare multisystem degenerative disorder due to mutations in valosin containing protein (VCP). VCP is a ubiquitously expressed protein that facilitates the degradation of proteins via the ubiquitin proteasome and autophagy pathways. Affected brain and muscle tissue in IBMPFD have ubiquitinated and TAR DNA binding protein- 43 (TDP-43) inclusions. In skeletal muscle, this pathology is consistent with IBM. While in the CNS, IBMPFD is a frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) subtype. Recent studies suggest that IBMPFD mutations in VCP disrupt its function in protein degradation. This review will explore the clinical phenotype and pathology of IBMPFD with an emphasis on central nervous system degeneration. In addition, we will discuss the current understanding regarding VCPs function in terminally differentiated tissue and how disease associated mutations result in both myo- and neurodegeneration.

Keywords: VCP, IBMPFD, FTD, ubiquitin, TDP-43, neurodegeneration, PDB, dilated cardiomyopathy, hepatic steatosis, phenotypic components, missense mutation, early psychotic features, IBM, FDG-PET