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.
|Lee, YouJin; Jonson, Per Harald; Sarparanta, Jaakko et al. (2018) TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations. J Clin Invest 128:1164-1177|
|Papadopoulos, Chrisovalantis; Kirchner, Philipp; Bug, Monika et al. (2017) VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy. EMBO J 36:135-150|
|Güttsches, Anne-Katrin; Brady, Stefen; Krause, Kathryn et al. (2017) Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis. Ann Neurol 81:227-239|
|Lee, YouJin; Chou, Tsui-Fen; Pittman, Sara K et al. (2017) Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination. Cell Rep 19:188-202|
|Oh, Sung-Hee; Choi, Yong-Bok; Kim, June-Hyun et al. (2017) Comparisons of ELISA and Western blot assays for detection of autophagy flux. Data Brief 13:696-699|
|Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|Bhattacharya, Martha R C; Geisler, Stefanie; Pittman, Sara K et al. (2016) TMEM184b Promotes Axon Degeneration and Neuromuscular Junction Maintenance. J Neurosci 36:4681-9|
|Weihl, Conrad C; Baloh, Robert H; Lee, Youjin et al. (2015) Targeted sequencing and identification of genetic variants in sporadic inclusion body myositis. Neuromuscul Disord 25:289-96|
|Bucelli, Robert C; Arhzaouy, Khalid; Pestronk, Alan et al. (2015) SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles. Neurology 85:665-74|
|Weihl, Conrad C; Iyadurai, Stanley; Baloh, Robert H et al. (2015) Autophagic vacuolar pathology in desminopathies. Neuromuscul Disord 25:199-206|
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