The Parkinson-associated human P5B-ATPase ATP13A2 protects against the iron-induced cytotoxicity

Rinaldi, Débora E.; Corradi, Gerardo R.; Cuesta, Lucía Martinez; Adamo, Hugo P.; Pinto, Felicitas de Tezanos

doi:10.1016/j.bbamem.2015.04.008

Cited by 36 publications

(19 citation statements)

References 57 publications

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“…C19orf12 may be involved in fatty acid biogenesis 41 and atp13a2 is a putative phospholipid flippase that translocates phospholipids across membranes 7, 61 and may protect against iron cytotoxicity through effects on membrane permeability. 62 …”

Section: Discussionmentioning

confidence: 99%

Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features

et al. 2016

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The ‘neurodegeneration with brain iron accumulation' (NBIA) disease family entails movement or cognitive impairment, often with psychiatric features. To understand how iron loading affects the brain, we studied mice with disruption of two iron regulatory genes, hemochromatosis (Hfe) and transferrin receptor 2 (Tfr2). Inductively coupled plasma atomic emission spectroscopy demonstrated increased iron in the Hfe−/− × Tfr2mut brain (P=0.002, n ≥5/group), primarily localized by Perls' staining to myelinated structures. Western immunoblotting showed increases of the iron storage protein ferritin light polypeptide and microarray and real-time reverse transcription-PCR revealed decreased transcript levels (P<0.04, n ≥5/group) for five other NBIA genes, phospholipase A2 group VI, fatty acid 2-hydroxylase, ceruloplasmin, chromosome 19 open reading frame 12 and ATPase type 13A2. Apart from the ferroxidase ceruloplasmin, all are involved in myelin homeostasis; 16 other myelin-related genes also showed reduced expression (P<0.05), although gross myelin structure and integrity appear unaffected (P>0.05). Overlap (P<0.0001) of differentially expressed genes in Hfe−/− × Tfr2mut brain with human gene co-expression networks suggests iron loading influences expression of NBIA-related and myelin-related genes co-expressed in normal human basal ganglia. There was overlap (P<0.0001) of genes differentially expressed in Hfe−/− × Tfr2mut brain and post-mortem NBIA basal ganglia. Hfe−/− × Tfr2mut mice were hyperactive (P<0.0112) without apparent cognitive impairment by IntelliCage testing (P>0.05). These results implicate myelin-related systems involved in NBIA neuropathogenesis in early responses to iron loading. This may contribute to behavioral symptoms in NBIA and hemochromatosis and is relevant to patients with abnormal iron status and psychiatric disorders involving myelin abnormalities or resistant to conventional treatments.

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Section: Discussionmentioning

confidence: 99%

Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features

et al. 2016

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“…Disease mutations have been shown to impair lysosomal function and to reduce the integrity of the lysosomal membrane 47, 48. So far, only one study has investigated the role of ATP13A2 in astrocytes [49].…”

Section: Parkinson’s Disease-related Genes and Their Functional Rolesmentioning

confidence: 99%

The Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis

Booth

Hirst

Wade‐Martins

2017

Trends in Neurosciences

436

366

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Astrocytes are the most populous glial subtype and are critical for brain function. Despite this, historically there have been few studies into the role that they may have in neurodegenerative diseases, such as Parkinson’s disease (PD). Recently, however, several studies have determined that genes known to have a causative role in the development of PD are expressed in astrocytes and have important roles in astrocyte function. Here, we review these recent developments and discuss their impact on our understanding of the pathophysiology of PD, and the implications that this might have for its treatment.

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“…1,2 Several reports show that the catalytic activity of ATP13A2 is required to protect cells against various insults like mitochondrial stress, a-synuclein toxicity and metal exposure (Zn 2C , Mn 2C and Fe 3C ). 1,6 It remains to be established whether all these various cytoprotective effects depend on the same N-terminal lipid switch. Besides lipid binding, the similarity of the N-terminus with the P1B-type heavy metal pumps may hint to a role of the membrane-associated N-terminus in substrate recognition and protein interactions 2 (Fig.…”

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confidence: 99%