Altered intracellular localization and valosin-containing protein (p97 VCP) interaction underlie ATP7A-related distal motor neuropathy

Yi, Ling, Donsante, Anthony, Kennerson, Marina L., Mercer, Julian F. B., Garbern, James Y. and Kaler, Stephen G. 2012, Altered intracellular localization and valosin-containing protein (p97 VCP) interaction underlie ATP7A-related distal motor neuropathy, Human molecular genetics, vol. 21, no. 8, pp. 1794-1807.

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Title Altered intracellular localization and valosin-containing protein (p97 VCP) interaction underlie ATP7A-related distal motor neuropathy
Author(s) Yi, Ling
Donsante, Anthony
Kennerson, Marina L.
Mercer, Julian F. B.
Garbern, James Y.
Kaler, Stephen G.
Journal name Human molecular genetics
Volume number 21
Issue number 8
Start page 1794
End page 1807
Total pages 14
Publisher Oxford University Press
Place of publication Oxford, England
Publication date 2012-04
ISSN 0964-6906
1460-2083
Keyword(s) copper-deficiency myeloneuropathy
inclusion-body myopathy
occipital-horn-syndrome
menkes-disease
neuron disease
frontotemporal dementia
regulated trafficking
hippocampal-neurons
muscular-atrophy
plasma-membrane
Summary ATP7A is a P-type ATPase that regulates cellular copper homeostasis by activity at the trans-Golgi network (TGN) and plasma membrane (PM), with the location normally governed by intracellular copper concentration. Defects in ATP7A lead to Menkes disease or its milder variant, occipital horn syndrome or to a newly discovered condition, ATP7A-related distal motor neuropathy (DMN), for which the precise pathophysiology has been obscure. We investigated two ATP7A motor neuropathy mutations (T994I, P1386S) previously associated with abnormal intracellular trafficking. In the patients' fibroblasts, total internal reflection fluorescence microscopy indicated a shift in steady-state equilibrium of ATP7AT994I and ATP7AP1386S, with exaggerated PM localization. Transfection of Hek293T cells and NSC-34 motor neurons with the mutant alleles tagged with the Venus fluorescent protein also revealed excess PM localization. Endocytic retrieval of the mutant alleles from the PM to the TGN was impaired. Immunoprecipitation assays revealed an abnormal interaction between ATP7AT994I and p97/VCP, an ubiquitin-selective chaperone which is mutated in two autosomal dominant forms of motor neuron disease: amyotrophic lateral sclerosis and inclusion body myopathy with early-onset Paget disease and fronto-temporal dementia. Small-interfering RNA (SiRNA) knockdown of p97/VCP corrected ATP7AT994I mislocalization. Flow cytometry documented that non-permeabilized ATP7AP1386S fibroblasts bound a carboxyl-terminal ATP7A antibody, consistent with relocation of the ATP7A di-leucine endocytic retrieval signal to the extracellular surface and partially destabilized insertion of the eighth transmembrane helix. Our findings illuminate the mechanisms underlying ATP7A-related DMN and establish a link between p97/VCP and genetically distinct forms of motor neuron degeneration.
Language eng
Field of Research 069999 Biological Sciences not elsewhere classified
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1 Refereed article in a scholarly journal
Persistent URL http://hdl.handle.net/10536/DRO/DU:30046901

Document type: Journal Article
Collection: School of Life and Environmental Sciences
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