Immunoreactivity of valosin-containing protein in sporadic amyotrophic lateral sclerosis and in a case of its novel mutant

Abstract

BackgroundMutations in the valosin-containing protein (VCP) gene were first found to cause inclusion- body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD). Mutations in the VCP gene were later reported to occur in familial amyotrophic lateral sclerosis (ALS). But the role of VCP in the neurodegenerative processes that occur in ALS remains unknown. The purpose of the present study was to elucidate the role of VCP in the neurodegeneration seen in sporadic and VCP mutant ALS.ResultsImmunohistochemistry demonstrated that the frequency of distinct VCP-positive nuclei of spinal motor neurons of patients with sporadic ALS (SALS) and the ALS with VCP novel mutation (ALS-VCP, M158V) was increased, compared with that of the control cases. No VCP-positive inclusion bodies were observed in SALS patients, a ALS-VCP patient or in control subjects. Neuropathologic examination of the ALS-VCP case showed loss of motor neurons, the presence of Bunina bodies, and degeneration of the corticospinal tracts. Bunina bodies detected in this case were confirmed to show immunohistochemical and ultrastructural features similar to those previously described. Furthermore, neuronal intracytoplasmic inclusions immunopositive for TAR DNA-binding protein 43 kDa (TDP-43), phosphorylated TDP-43, ubiquitin (Ub), p62, and optineurin were identified in the spinal and medullary motoneurons, but not in the neocortex. Gene analysis of this ALS-VCP patient confirmed the de novo mutation of M158V, which was not found in control cases; and bioinformatics using several in silico analyses showed possible damage to the structure of VCP. Immunocytochemical study of cultured cells showed increased cytoplasmic translocation of TDP-43 in cells transfected with several mutant VCP including our patient’s compared with wild-type VCP.ConclusionThese findings support the idea that VCP is associated with the pathomechanism of SALS and familial ALS with a VCP mutation, presumably acting through a dominant-negative mechanism.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0172-0) contains supplementary material, which is available to authorized users.

ALS‐Associated Endoplasmic Reticulum Proteins in Denervated Skeletal Muscle: Implications for Motor Neuron Disease Pathology

“…In this context, it is interesting to mention other proteins that are linked to selective damage to both the neuronal and muscle fibre component of the neuromuscular axis. For example, mutations in the ATP‐driven chaperone valosin‐containing protein (VCP) can lead to vacuolar myopathy, ALS, FTLD or combinations thereof . Similarly, mutation of the nuclear matrix protein Matrin‐3 may lead to either vacuolar myopathy or ALS ; recent evidence suggests that Matrin‐3 binds to ER chaperones such as GRP78 .…”

Disrupted neuronal trafficking in amyotrophic lateral sclerosis

“…TDP-43 aggregates colocalize with autophagy markers such as LC3 and p62/SQSTM1 (Sequestosome 1 (SQSTM1, also known as ubiquitin-binding protein p62) [ 70 ]. Furthermore, VCP and optineurin (OPTN), which colocalize with TDP-43, p62/SQSTM1, and ubiquitin, colocalize in spinal motor neurons of sporadic ALS patients [ 11 ]. Furthermore, elevated levels of LC3 have been found in skin biopsies of patients carrying the TDP-43 A315T mutation, suggesting that ALS-associated TDP-43 mutations may enhance autophagy [ 180 ].…”

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

“…Furthermore, cytoplasmic translocation of TDP-43 is observed in cells expressing mutant VCP (Ayaki et al, 2014) and in lymphocytes and monocytes from fALS patients (De Marco et al, 2017). TDP-43 also mislocalizes to the cytosol upon VCP-mediated autophagy dysfunction (Ju et al, 2009; Tresse et al, 2010).…”