Decreases in valosin-containing protein result in increased levels of tau phosphorylated at Ser^262/356

Abstract

VCP/p97 is a multifunctional AAA+-ATPase involved in vesicle fusion, proteasomal degradation, and autophagy. Reported dysfunctions of these processes in Alzheimer disease (AD), along with the linkage of VCP/p97 to inclusion body myopathy with Paget’s disease and frontotemporal dementia (IBMPFD) led us to examine the possible linkage of VCP to the AD-relevant protein, tau. VCP levels were reduced in AD brains, but not in the cerebral cortex of an AD mouse model, suggesting that VCP reduction occurs upstream of tau pathology. Genetic reduction of VCP in a primary neuronal model led to increases in the levels of tau phosphorylated at Ser262/356, indicating that VCP may be involved in regulating post-translational processing of tau in AD, demonstrating a possible functional linkage between tau and VCP.

Tau Clearance Mechanisms and Their Possible Role in the Pathogenesis of Alzheimer Disease

“…However, the levels of tau phosphorylated at KXGS sites within the repeat domain were not reduced by geldanamycin treatment. In agreement with those findings, inhibiting autophagy in primary rat cortical neurons with 3-MA resulted in the selective accumulation of tau phosphorylated at the KXGS motif S262 (recognized by the 12E8 antibody) (106). Additionally, in a hippocampal slice preparation, induction of autophagy by treatment with methylene blue led to a decrease in phosphorylated tau and insoluble tau without an effect on total tau (95).…”

Inhibitors of the AAA+ Chaperone p97

“…Along with its role in cancer, p97 has been implicated both directly and indirectly in neurodegenerative proteinopathies [ 3 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Genetic investigations of patients have revealed a series of mutations in p97 that lead to the rare autosomal dominant condition known as inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) [ 73 ].…”

“…Over the last decade, genetic and biochemical investigations have revealed the ATPase associated with various cellular activities (AAA+) chaperone p97, also called valosin containing protein (VCP) and Cdc48, as a potential therapeutic target for cancer [ 1 , 2 , 3 , 4 , 5 , 6 ]. In addition, p97 has been linked both directly and indirectly to neurodegenerative disorders caused by proteostatic malfunction [ 3 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. This information has led the drive within both academic and industrial laboratories to identify small molecules that can inhibit specific aspects of p97 function [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”

VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo

“…Muscle biopsies from patients with VCP-related disease display an accumulation of cytoplasmic poly-ubiquitin aggregates ( Watts et al, 2004 ; Weihl et al, 2009 ; Dolan et al, 2011 ), suggesting a defect in protein clearance. This led us to explore the intersection of the observed tubular lysosomal network and autophagy.…”

“…Muscle weakness is the first presenting symptom in over 50% of VCP disease patients ( Weihl et al, 2009 ), yet very little is known about the muscle pathology of VCP-related diseases. Muscle biopsies from patients with VCP-related diseases display an accumulation of cytoplasmic poly-ubiquitin aggregates ( Watts et al, 2004 ; Weihl et al, 2009 ; Dolan et al, 2011 ), suggesting a major defect in protein clearance. VCP is an AAA-ATPase that has essential functions in ubiquitin-dependent proteolysis.…”