One age associated muscle disorder is due to mutations in valosin containing protein (VCP) which causes IBMPFD/ALS or inclusion body myopathy (IBM) associated with Paget's disease of the bone (PDB), fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Muscle weakness is the most prevalent phenotypic feature. Although IBMPFD itself is rare, the culmination of each component (IBM, PDB, FTD and ALS) makes its incidence more common in the general population. VCP mutations disrupt autophagosome maturation resulting in dysfunctional autophagy and muscle weakness. In addition, they disrupt mTORC1 signaling. We propose to 1) identify the molecular complex essential for VCP mediation autophagy;2) understand the role for VCP in amino acid stimulated mTORC1 activity. 3) Modulate mTORC1 activity as a therapeutic intervention in IBMPFD/ALS. This proposal will extend the observations and published results from the applicant over the past 5 years.
Pathologic protein inclusions accumulate in many divergent disease states associated with aging like inclusion body myositis and dementia. We hypothesize that an impairment in autophagy and autophagy signaling pathways conferred by mutations in the protein VCP results in inclusion body myopathy associated with Paget's disease of the bone, fronto-temporal dementia and amyotrophic lateral sclerosis (IBMPFD/ALS). Understanding IBMPFD/ALS will lend insight into the treatment of other more common age related disorders.
|Meyer, Hemmo; Weihl, Conrad C (2014) The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis. J Cell Sci 127:3877-83|
|Chou, Tsui-Fen; Bulfer, Stacie L; Weihl, Conrad C et al. (2014) Specific inhibition of p97/VCP ATPase and kinetic analysis demonstrate interaction between D1 and D2 ATPase domains. J Mol Biol 426:2886-99|
|Stein, Kevin C; Bengoechea, Rocio; Harms, Matthew B et al. (2014) Myopathy-causing mutations in an HSP40 chaperone disrupt processing of specific client conformers. J Biol Chem 289:21120-30|
|Gonzalez, Michael A; Feely, Shawna M; Speziani, Fiorella et al. (2014) A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 disease. Brain 137:2897-902|
|Bibee, Kristin P; Cheng, Ya-Jian; Ching, James K et al. (2014) Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function. FASEB J 28:2047-61|
|Udan-Johns, Maria; Bengoechea, Rocio; Bell, Shaughn et al. (2014) Prion-like nuclear aggregation of TDP-43 during heat shock is regulated by HSP40/70 chaperones. Hum Mol Genet 23:157-70|
|Weihl, Conrad C (2013) Monitoring autophagy in the treatment of protein aggregate diseases: steps toward identifying autophagic biomarkers. Neurotherapeutics 10:383-90|
|Ching, James K; Weihl, Conrad C (2013) Rapamycin-induced autophagy aggravates pathology and weakness in a mouse model of VCP-associated myopathy. Autophagy 9:799-800|
|Ching, James K; Elizabeth, Sarita V; Ju, Jeong-Sun et al. (2013) mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy. Hum Mol Genet 22:1167-79|
|Benatar, Michael; Wuu, Joanne; Fernandez, Catalina et al. (2013) Motor neuron involvement in multisystem proteinopathy: implications for ALS. Neurology 80:1874-80|
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