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Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking

Behne R, Teinert J, Wimmer M, D'Amore A, Davies AK, Scarrott JM, Eberhardt K, Brechmann B, Chen IPF, Buttermore ED, Barrett L, Dwyer S, Chen T, Hirst J, Wiesener A, Segal D, Martinuzzi A, Duarte ST, Bennett JT, Bourinaris T, Houlden H, Roubertie A, Santorelli FM, Robinson M, Azzouz M, Lipton JO, Borner GH, Sahin M, Ebrahimi-Fakhari D (2020)

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Publication Type: Journal article

Publication year: 2020

Journal

Book Volume: 29

Pages Range: 320-334

Journal Issue: 2

DOI: 10.1093/hmg/ddz310

Abstract

Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3-5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.

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How to cite

APA:

Behne, R., Teinert, J., Wimmer, M., D'Amore, A., Davies, A.K., Scarrott, J.M.,... Ebrahimi-Fakhari, D. (2020). Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking. Human Molecular Genetics, 29(2), 320-334. https://doi.org/10.1093/hmg/ddz310

MLA:

Behne, Robert, et al. "Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking." Human Molecular Genetics 29.2 (2020): 320-334.

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