TY - JOUR
T1 - Golgi-dependent copper homeostasis sustains synaptic development and mitochondrial content
AU - Hartwig, Cortnie
AU - Méndez, Gretchen MacÍas
AU - Bhattacharjee, Shatabdi
AU - Vrailas-Mortimer, Alysia D.
AU - Zlatic, Stephanie A.
AU - Freeman, Amanda A.H.
AU - Gokhale, Avanti
AU - Concilli, Mafalda
AU - Werner, Erica
AU - Savas, Christie Sapp
AU - Rudin-Rush, Samantha
AU - Palmer, Laura
AU - Shearing, Nicole
AU - Margewich, Lindsey
AU - McArthy, Jacob
AU - Taylor, Savanah
AU - Roberts, Blaine
AU - Lupashin, Vladimir
AU - Polishchuk, Roman S.
AU - Cox, Daniel N.
AU - Jorquera, Ramon A.
AU - Faundez, Victor
N1 - Publisher Copyright:
Copyright © 2021 the authors.
PY - 2021/1/13
Y1 - 2021/1/13
N2 - Rare genetic diseases preponderantly affect the nervous system causing neurodegeneration to neurodevelopmental disorders. This is the case for both Menkes and Wilson disease, arising from mutations in ATP7A and ATP7B, respectively. The ATP7A and ATP7B proteins localize to the Golgi and regulate copper homeostasis. We demonstrate genetic and biochemical interactions between ATP7 paralogs with the conserved oligomeric Golgi (COG) complex, a Golgi apparatus vesicular tether. Disruption of Drosophila copper homeostasis by ATP7 tissue-specific transgenic expression caused alterations in epidermis, aminergic, sensory, and motor neurons. Prominent among neuronal phenotypes was a decreased mitochondrial content at synapses, a phenotype that paralleled with alterations of synaptic morphology, transmission, and plasticity. These neuronal and synaptic phenotypes caused by transgenic expression of ATP7 were rescued by downregulation of COG complex subunits. We conclude that the integrity of Golgi-dependent copper homeostasis mechanisms, requiring ATP7 and COG, are necessary to maintain mitochondria functional integrity and localization to synapses.
AB - Rare genetic diseases preponderantly affect the nervous system causing neurodegeneration to neurodevelopmental disorders. This is the case for both Menkes and Wilson disease, arising from mutations in ATP7A and ATP7B, respectively. The ATP7A and ATP7B proteins localize to the Golgi and regulate copper homeostasis. We demonstrate genetic and biochemical interactions between ATP7 paralogs with the conserved oligomeric Golgi (COG) complex, a Golgi apparatus vesicular tether. Disruption of Drosophila copper homeostasis by ATP7 tissue-specific transgenic expression caused alterations in epidermis, aminergic, sensory, and motor neurons. Prominent among neuronal phenotypes was a decreased mitochondrial content at synapses, a phenotype that paralleled with alterations of synaptic morphology, transmission, and plasticity. These neuronal and synaptic phenotypes caused by transgenic expression of ATP7 were rescued by downregulation of COG complex subunits. We conclude that the integrity of Golgi-dependent copper homeostasis mechanisms, requiring ATP7 and COG, are necessary to maintain mitochondria functional integrity and localization to synapses.
KW - ATP7A
KW - Copper
KW - Golgi
KW - Menkes
KW - Mitochondria
KW - Wilson
UR - http://www.scopus.com/inward/record.url?scp=85100069313&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1284-20.2020
DO - 10.1523/JNEUROSCI.1284-20.2020
M3 - Article
C2 - 33208468
AN - SCOPUS:85100069313
SN - 0270-6474
VL - 41
SP - 215
EP - 233
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 2
ER -