TY - JOUR
T1 - Endocytosis regulates TDP-43 toxicity and turnover
AU - Liu, Guangbo
AU - Coyne, Alyssa N.
AU - Pei, Fen
AU - Vaughan, Spencer
AU - Chaung, Matthew
AU - Zarnescu, Daniela C.
AU - Buchan, J. Ross
N1 - Funding Information:
We thank Aaron Gitler, Tricia Serio, and Daniel Klionsky for providing various yeast plasmids, and Kun-Liang Guan and Chengyu Liang for providing various mammalian cell plasmids. We thank Torsten Falk for providing SH-SY5Y cells, and the Southern Arizona VA Healthcare Agency for providing us with ALS and control patient tissue. We thank J. Paul Taylor and Takeshi Iwatsubo for provision of untagged WT and G298S TDP-43, respectively. We thank Roy Parker, Hanna Fares, Anita Koshy, May Khanna, Felicia Goodrum, and Tricia Serio for helpful manuscript feedback. This work was supported by funds to J.R.B. from NIH RO1-GM1145664 and the ALS Association, and to D.C.Z. from NIH RO1 NS091299. S.V. and M.C. were supported in part by internal funds from the Provost through the University of Arizona Undergraduate Biology Research Program.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. ALS-affected motor neurons exhibit aberrant localization of a nuclear RNA binding protein, TDP-43, into cytoplasmic aggregates, which contributes to pathology via unclear mechanisms. Here, we demonstrate that TDP-43 turnover and toxicity depend in part upon the endocytosis pathway. TDP-43 inhibits endocytosis, and co-localizes strongly with endocytic proteins, including in ALS patient tissue. Impairing endocytosis increases TDP-43 toxicity, aggregation, and protein levels, whereas enhancing endocytosis reverses these phenotypes. Locomotor dysfunction in a TDP-43 ALS fly model is also exacerbated and suppressed by impairment and enhancement of endocytic function, respectively. Thus, endocytosis dysfunction may be an underlying cause of ALS pathology.
AB - Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. ALS-affected motor neurons exhibit aberrant localization of a nuclear RNA binding protein, TDP-43, into cytoplasmic aggregates, which contributes to pathology via unclear mechanisms. Here, we demonstrate that TDP-43 turnover and toxicity depend in part upon the endocytosis pathway. TDP-43 inhibits endocytosis, and co-localizes strongly with endocytic proteins, including in ALS patient tissue. Impairing endocytosis increases TDP-43 toxicity, aggregation, and protein levels, whereas enhancing endocytosis reverses these phenotypes. Locomotor dysfunction in a TDP-43 ALS fly model is also exacerbated and suppressed by impairment and enhancement of endocytic function, respectively. Thus, endocytosis dysfunction may be an underlying cause of ALS pathology.
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U2 - 10.1038/s41467-017-02017-x
DO - 10.1038/s41467-017-02017-x
M3 - Article
C2 - 29233983
AN - SCOPUS:85037717619
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2092
ER -