Autophagy is dysfunctional in many degenerative diseases including myopathies. Mutations in valosin containing protein (VCP) cause inclusion body myopathy (IBM) associated with paget's disease of the bone, fronto-temporal dementia and amyotrophic lateral sclerosis (IBMPFD/ALS). VCP is necessary for protein degradation via the proteasome and lysosome. IBMPFD/ALS mutations in VCP disrupt autophagosome and endosome maturation resulting in vacuolation, weakness and muscle atrophy. To understand the regulation of autophagy in VCP-IBM muscle, we examined the AKT/FOXO3 and mTOR pathways. Basal Akt and FOXO3 phosphorylation was normal. In contrast, the phosphorylation of mTOR targets was decreased. Consistent with this, global protein translation was diminished and autophagosome biogenesis was increased in VCP-IBM muscle. Further mTORC1 inhibition with rapamycin hastened weakness, atrophy and vacuolation in VCP-IBM mice. This was accompanied by the accumulation of autophagic substrates such as p62, LC3II and ubiquitinated proteins. The decrease in mTOR signaling was partially rescued by insulin and to a lesser extent by amino acid stimulation in VCP-IBM muscle. Cells expressing catalytically inactive VCP or treated with a VCP inhibitor also failed to activate mTOR upon nutrient stimulation. Expression of a constitutively active Rheb enhanced mTOR activity and increased fiber size in VCP-IBM mouse skeletal muscle. These studies suggest that VCP mutations may disrupt mTOR signaling and contribute to IBMPFD/ALS disease pathogenesis. Treatment of some autophagic disorders with mTOR inhibitors such as rapamycin may worsen disease.
"TOR pathway has been shown to be involved regulating aging and a number of diseases. Reduced TOR signaling has been shown in case of VCP mediated ALS (Ching et al., 2013). Feeding SOD1 G93A mutant mice with rapamycin, an inhibitor of TORC1 shortens life span (Zhang et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective death of motor neurons. In 5–10% of the familial cases, the disease is inherited because of mutations. One such mutation, P56S, was identified in human VAPB that behaves in a dominant negative manner, sequestering wild type protein into cytoplasmic inclusions.
We have conducted a reverse genetic screen to identify interactors of Drosophila VAPB. We screened 2635 genes and identified 103 interactors, of which 45 were enhancers and 58 were suppressors of VAPB function. Interestingly, the screen identified known ALS loci – TBPH, alsin2 and SOD1. Also identified were genes involved in cellular energetics and homeostasis which were used to build a gene regulatory network of VAPB modifiers. One key modifier identified was Tor, whose knockdown reversed the large bouton phenotype associated with VAP(P58S) expression in neurons. A similar reversal was seen by over-expressing Tuberous Sclerosis Complex (Tsc1,2) that negatively regulates TOR signaling as also by reduction of S6K activity. In comparison, the small bouton phenotype associated with VAP(wt) expression was reversed with Tsc1 knock down as well as S6K-CA expression. Tor therefore interacts with both VAP(wt) and VAP(P58S), but in a contrasting manner. Reversal of VAP(P58S) bouton phenotypes in larvae fed with the TOR inhibitor Rapamycin suggests upregulation of TOR signaling in response to VAP(P58S) expression.
The VAPB network and further mechanistic understanding of interactions with key pathways, such as the TOR cassette, will pave the way for a better understanding of the mechanisms of onset and progression of motor neuron disease.
Biology Open 11/2014; 3(11):1127-38. DOI:10.1242/bio.201410066 · 2.42 Impact Factor
"On light microscopy, EPG5-related myopathy is characterized by variable degrees of type 1 predominance, type 1 atrophy and fibre type disproportion, central nuclei, vacuoles and increased glycogen storage . On electron microscopy, abnormalities of mitochondrial distribution and structures are a common additional finding . These findings suggest a histopathological overlap between EPG5-related Vici syndrome and a wide range of neuromuscular disorders where aberrant autophagy has been implicated as an important secondary mechanism, including vacuolar myopathies, centronuclear myopathies and glycogen storage disorders; investigation of the EPG5-related myopathy is thus likely also to advance understanding of these conditions, and to inform therapy development. "
"Ingenuity Pathway Analysis (IPA) showed that endoplasmic reticulum (ER) stress response-, NRF2 mediated oxidative stress-, PTEN-, integrin- and EIF2- signalling pathways were among the most clearly affected pathways in TMD (Fig. 2A, 2B & 2C). There were also a range of pathway changes that have been identified in other myopathies with rimmed vacuoles such as; SAPK/JNK apoptosis- , p70S6K- , , protein ubiquitination- ,  and mitochondrial dysfunction- ,  signalling (Fig. 2B, 2C, & 2D). "
[Show abstract][Hide abstract] ABSTRACT: Tibial muscular dystrophy (TMD) is a late onset, autosomal dominant distal myopathy that results from mutations in the two last domains of titin. The cascade of molecular events leading from the causative Titin mutations to the preterm death of muscle cells in TMD is largely unknown. In this study we examined the mRNA and protein changes associated with the myopathology of TMD. To identify these components we performed gene expression profiling using muscle biopsies from TMD patients and healthy controls. The profiling results were confirmed through quantitative real-time PCR and protein level analysis. One of the pathways identified was activation of endoplasmic reticulum (ER) stress response. ER stress activates the unfolded protein response (UPR) pathway. UPR activation was supported by elevation of the marker genes HSPA5, ERN1 and the UPR specific XBP1 splice form. However, UPR activation appears to be insufficient to correct the protein abnormalities causing its activation because degenerative TMD muscle fibres show an increase in ubiquitinated protein inclusions. Abnormalities of VCP-associated degradation pathways are also suggested by the presence of proteolytic VCP fragments in western blotting, and VCP's accumulation within rimmed vacuoles in TMD muscle fibres together with p62 and LC3B positive autophagosomes. Thus, pathways controlling turnover and degradation, including autophagy, are distorted and lead to degeneration and loss of muscle fibres.
PLoS ONE 03/2014; 9(3):e90819. DOI:10.1371/journal.pone.0090819 · 3.23 Impact Factor
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