The Parkinson-associated human P5B-ATPase ATP13A2 modifies lipid homeostasis

Marcos, Alejandra; Corradi, Gerardo R.; Mazzitelli, Luciana R.; Casali, Cecilia I.; Tome, María del Carmen Fernández; Adamo, Hugo P.; Pinto, Felicitas de Tezanos

doi:10.1016/j.bbamem.2019.05.015

Cited by 15 publications

(13 citation statements)

References 65 publications

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“…ATP13A2 appears to promote autophagosome-lysosome fusion by facilitating recruitment of histone deacetylase 6 (HDAC6) to the lysosomal membrane [145]. A role for ATP13A2 in membrane trafficking and in the promotion of the autophagy-lysosomal pathway is consistent with the observations of altered lysosomal morphology, storage material accumulation, a-synuclein aggregation, and impaired mitochondrial function in ATP13A2-deficiency disease models and patient cells [137,138,[146][147][148][149][150][151][152][153].…”

Section: Mfsd8-supporting

confidence: 54%

Moving towards a new era of genomics in the neuronal ceroid lipofuscinoses

Butz

Chandrachud

Mole

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The neuronal ceroid lipofuscinoses (NCL) are a group of disorders defined by shared clinical and pathological features, including seizures and progressive decline in vision, neurocognition, and motor functioning, as well as accumulation of autofluorescent lysosomal storage material, or 'ceroid lipofuscin'. Research has revealed thirteen distinct genetic subtypes. Precisely how the gene mutations lead to the clinical phenotype is still incompletely understood, but recent research progress is starting to shed light on disease mechanisms, in both gene-specific and shared pathways. As the application of new sequencing technologies to genetic disease diagnosis has grown, so too has the spectrum of clinical phenotypes caused by mutations in the NCL genes. Most genes causing NCL have probably been identified, underscoring the need for a shift towards applying genomics approaches to achieve a deeper understanding of the molecular basis of the NCLs and related disorders. Here, we summarize the current understanding of the thirteen identified NCL genes and the proteins they encode, touching upon the spectrum of clinical manifestations linked to each of the genes, and we highlight recent progress leading to a broader understanding of key pathways involved in NCL disease pathogenesis and commonalities with other neurodegenerative diseases.

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Section: Mfsd8-supporting

confidence: 54%

Moving towards a new era of genomics in the neuronal ceroid lipofuscinoses

Butz

Chandrachud

Mole

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Still, additional studies involving multiple -omics approaches are necessary to allow a better characterization of the role of lipids in PD. Such studies will be of particular interest since several familial PD genes, such as LRRK2 [108], PINK1 [109], DJ1 [110], ATP13A2 [111], PLA2G6 [112] and ATXN2 [113], are known to modulate various lipid metabolism pathways.…”

Section: Discussionmentioning

confidence: 99%

Explorative Combined Lipid and Transcriptomic Profiling of Substantia Nigra and Putamen in Parkinson’s Disease

Brouwers

Wieringa

Martens³

2020

Cells

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Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons from the substantia nigra (SN) that project to the dorsal striatum (caudate-putamen). To better understand the molecular mechanisms underlying PD, we performed combined lipid profiling and RNA sequencing of SN and putamen samples from PD patients and age-matched controls. SN lipid analysis pointed to a neuroinflammatory component and included elevated levels of the endosomal lipid Bis (Monoacylglycero)Phosphate 42:8, while two of the three depleted putamen lipids were saturated sphingomyelin species. Remarkably, we observed gender-related differences in the SN and putamen lipid profiles. Transcriptome analysis revealed that the top-enriched pathways among the 354 differentially expressed genes (DEGs) in the SN were “protein folding” and “neurotransmitter transport”, and among the 261 DEGs from putamen “synapse organization”. Furthermore, we identified pathways, e.g., “glutamate signaling”, and genes, encoding, e.g., an angiotensin receptor subtype or a proprotein convertase, that have not been previously linked to PD. The identification of 33 genes that were common among the SN and putamen DEGs, which included the α-synuclein paralog β-synuclein, may contribute to the understanding of general PD mechanisms. Thus, our proof-of-concept data highlights new genes, pathways and lipids that have not been explored before in the context of PD.

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“…ATPase cation transporting protein 13A2 (ATP13A2) functions in cation transport within the cell. Mutations to ATP13A2 are associated with PD and overexpression of ATP13A2 showed a decrease in various forms of lipids in vitro (Marcos et al, 2019). When looking at these findings together, it is evident that LDs and lipid homeostasis play a more significant role in PD than originally thought.…”

Section: Parkinson's Diseasementioning

confidence: 95%

Lipid Droplets in Neurodegenerative Disorders

et al. 2020

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Knowledge of lipid droplets (LDs) has evolved from simple depots of lipid storage to dynamic and functionally active organelles involved in a variety of cellular functions. Studies have now informed significant roles for LDs in cellular signaling, metabolic disease, and inflammation. While lipid droplet biology has been well explored in peripheral organs such as the liver and heart, LDs within the brain are relatively understudied. The presence and function of these dynamic organelles in the central nervous system has recently gained attention, especially in the context of neurodegeneration. In this review, we summarize the current understanding of LDs within the brain, with an emphasis on their relevance in neurodegenerative diseases.

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The Parkinson-associated human P5B-ATPase ATP13A2 modifies lipid homeostasis

Cited by 15 publications

References 65 publications

Moving towards a new era of genomics in the neuronal ceroid lipofuscinoses

Moving towards a new era of genomics in the neuronal ceroid lipofuscinoses

Explorative Combined Lipid and Transcriptomic Profiling of Substantia Nigra and Putamen in Parkinson’s Disease

Lipid Droplets in Neurodegenerative Disorders

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