The overarching goal of R01 renewal is to continue our work on a multisystem degenerative disorder with muscle weakness and fronto-temporal dementia. VCP pathologies are unified by ubiquitin and TDP43 inclusions. VCP disease mutations affect multiple cellular process such as autophagy and endolysosomal trafficking that converge at the lysosome. Recently we have identified a critical role for VCP in maintaining lysosome integrity that is impaired in the setting of disease mutatins. We plan to perform the following aims will 1) Evaluate the role of VCP in lysophagy in neurons and muscle; 2) Evaluate lysosome mediated signaling pathways such as mTORC1 and TFEB in the brains of mice with VCP disease mutations; 3) Explore the role of VCP in the endolysosomal escape of proteopathic seeds. Upon completion we will understand the role of VCP in lysosomal homeostasis and how this is affected by VCP disease mutations in muscle and neurons.
| 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 |
| Zhang, Xiaoyi; Gui, Lin; Zhang, Xiaoyan et al. (2015) Altered cofactor regulation with disease-associated p97/VCP mutations. Proc Natl Acad Sci U S A 112:E1705-14 |
| Crisp, Matthew J; Mawuenyega, Kwasi G; Patterson, Bruce W et al. (2015) In vivo kinetic approach reveals slow SOD1 turnover in the CNS. J Clin Invest 125:2772-80 |
| Jerath, Nivedita U; Crockett, Cameron D; Moore, Steven A et al. (2015) Rare Manifestation of a c.290 C>T, p.Gly97Glu VCP Mutation. Case Rep Genet 2015:239167 |
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