Valosin-containing protein and the pathogenesis of frontotemporal dementia associated with inclusion body myopathy

Abstract

Frontotemporal dementia with inclusion body myopathy and Paget's disease of bone (IBMPFD) is a rare, autosomal dominant disorder caused by mutations in the gene valosin-containing protein (VCP). The CNS pathology is characterized by a novel pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions without VCP mutations. Yet, the ubiquitin-positive inclusions in IBMPFD also stain for TAR DNA binding protein, a feature that links this rare disease with the pathology associated with the majority of sporadic FTD as well as disease resulting from different genetic alterations. VCP, a member of the AAA-ATPase gene family, associates with a plethora of protein adaptors to perform a variety of cellular processes including Golgi assembly/disassembly and regulation of the ubiquitin-proteasome system. However, the mechanism whereby mutations in VCP lead to CNS, muscle, and bone disease is largely unknown. In this report, we review current literature on IBMPFD, focusing on the pathology of the disease and the biology of VCP with respect to IBMPFD.

Affinity Capture and Identification of Host Cell Factors Associated with Hepatitis C Virus (+) Strand Subgenomic RNA

“…Cellular factors involved in a variety of transport functions were also affinity-captured with the HCV RNA genome. These are UBQRC2, a subunit of the mitochondrial respiratory chain protein ubiquinol-cytochrome-c reductase complex III, which is involved in electron transfer from ubiquinol to cytochrome c (63); nucleoporin-like protein, which is required for the export of mRNAs containing poly(A) tails from the nucleus into the cytoplasm (64), as well as docking of HIV-1 Vpr at the nuclear envelope (65); and valosin-containing protein (VCP), also known as transitional endoplasmic reticulum ATPase (TER ATPase) or p97, which is an enzyme involved in vesicle transport and fusion, 26 S proteasome function, assembly of per-oxisomes, and various cellular events that are regulated during mitosis (66). These cellular factors also include Caprin 1, a cell cycle-associated phosphoprotein required for normal progression through the G 1 -S phase of the cell cycle (67).…”

Engineered Interfaces of an AAA+ ATPase Reveal a New Nucleotide-dependent Coordination Mechanism

“…Mutations in these proteins have been reported in several human diseases, including fronto-temporal dementia with inclusion body myopathy and Paget disease of bone, hereditary spastic paraparesis, dystonia, and prostate cancer (1)(2)(3)(4)(5)(6)(7)(8). However, the underlying mechanisms by which these mutations affect the AAA ϩ ATPase (resulting in these diseases) are largely unknown, reducing drastically the possibility of treatment.…”

A Brazilian family with hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia

“…Published April 11, 2011. Hereditary inclusion body myopathy associated with Paget disease of bone (PDB) and frontotemporal dementia (FTD; IBMPFD, MIM 167320) is a rare, highly penetrant, progressive and ultimately lethal multisystemic disorder. It is characterized by a triad of clinical features: 1) proximal and distal muscle weakness due to myopathy; 2) early age of onset of PDB, and 3) FTD (1,2). Inclusion body myopathy is the most common clinical feature of IBMPFD, occurring in about 90% of the patients.…”

“…Other symptoms associated with PDB are long and cranial bone deformations, pathological fractures and spine and hip pain. Elevated levels of alkaline phosphatase, urine pydridinoline and deoxypydridinoline are also common (1,4).…”