ATP13A2

Official Full Name

ATPase cation transporting 13A2

Organism

Homo sapiens

GeneID

23400

Background

This gene encodes a member of the P5 subfamily of ATPases which transports inorganic cations as well as other substrates. Mutations in this gene are associated with Kufor-Rakeb syndrome (KRS), also referred to as Parkinson disease 9. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2008]

Synonyms

CLN12; KRPPD; PARK9; SPG78; HSA9947;

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Detailed Information

The protein encoded by the ATP13A2 gene belongs to the P-type ATPases protein superfamily, which is mainly involved in the transmembrane transport of inorganic ions. The ATP13A2 protein may have the function of transporting Mn. The P-type ATPase is a large family of proteins involved in the transport of cations and other substrates on the cell membrane by utilizing the energy of the ATP hydrolase. Functionally, they are involved in important cellular processes, including vesicle transport and maintenance of cell membrane excitability. In the human brain, ATP13A2 is highly expressed in neurons in the ventral midbrain but is also found in the basal ganglia (palm and nucleus), hippocampus, cortex, and cerebellum. Considering the location of the ventral midbrain, it suggests that a decrease in ATP13A2 may cause a fragile area in the area, making it susceptible to moderate attack. Murphy et al found that ATP13A2 protein levels were significantly reduced in synucleinopathies. Deletion of ATP13A2 expression is associated with mitochondrial division and dysfunction. Overexpression of ATP13A2 protects cells and significantly reduces the loss of degeneration of dopaminergic neurons induced by α-synuclein.

Fleming suggested that in humans, complete loss of ATP13A2 functional mutations is associated with neurodegenerative diseases kufor-rakeb syndrome and neuronal waxy lipofuscinosis. The former is classified as the genetic form of Parkinson's disease (PD). In addition, the ATP13A2 polymorphism has been shown to alter the neurotoxic effects of manganese in the elderly population. In vitro, deletion of ATP13A2 is associated with increased manganese, αSyn toxicity, and mitochondrial debris.

ATP13A2 Gene Mutation and Clinical Manifestations

The 3.8 kb mRNA of the ATP13A2 gene is widely expressed in various tissues, and the expression levels are different in different tissues, and high levels are expressed in the adult central nervous system sub-region (including the substantia nigra). This suggests that the ATP13A2 gene may be a housekeeping gene, which is functionally tissue-specific. Studies have shown that the mRNA of the wild-type ATP13A2 protein is mainly expressed in the brain, especially the substantia nigra and striatum, and is up-regulated in the brain of sporadic late-onset Parkinson's patients. The study found that the defect of ATP13A2 is caused by a single nucleotide deletion, resulting in a frameshift mutation or a single nucleotide substitution. Further studies have revealed various mutations that cause ATP13A2 to lose its function.

The mutation of ATP13A2 is associated with autosomal recessive early-onset Parkinson's disease and is characterized by levodopa-responsive Parkinson's disease, supranuclear gaze paralysis, pyramidal tract sign, and Kufor- Rakeb Syndrome (KRS) with cognitive dysfunction. Sato et al. performed a haploid analysis of 117 patients with early Parkinson's disease. They showed homozygous at the PARK9 locus and directly sequenced 29 exons of ATP13A2. Of the 117 patients, 28 patients showed homozygosity at the PARK9 locus. It is worth noting that in patients with ATP13A2 mutations, a decrease in mental symptoms and/or cognitive ability is very common.

Pathogenic Mechanism of ATP13A2 Mutation

The function of ATP13A2 is still largely unknown but is involved in protein degradation through autophagy and lysosomal pathways. In vitro experiments have shown that a variety of factors contribute to the role of ATP13A2 in the pathogenesis of PD, including autophagy, lysosomal dysfunction, α-synuclein accumulation, mitochondrial bioenergy, and manganese and zinc homeostasis.

Overexpression experiments revealed that the wild-type ATP13A2 protein subcellular is localized to lysosomes. Several studies have shown that lysosomes are closely related to the pathogenesis of PD, such as the degradation of the α-synuclein protein. The unstable ATP13A2 gene mutation is retained in the endoplasmic reticulum and is degraded by the proteasome, thereby increasing endoplasmic reticulum stress and increasing the burden of the proteasome degradation pathway. These suggest that ATP13A2 protein may participate in the pathogenesis of PD through the lysosomal pathway and the proteasome pathway.

The role of ATP13A2 in the maintenance of lysosomes and late endosomes may well exceed the scope of autophagy. Due to its role in regulating lysosomes, it is easy to conclude that ATP13A2 may play an important role in macroscopic, microscopic and molecular chaperone-mediated autophagy. Bento et al. showed that ATP13A2 can mediate autophagy through transcriptional and post-translational regulation of SYT11, a well-recognized PD risk site involved in the lysosomal action. This study suggests that a deficiency in ATP13A2 results in a decrease in SYT11 expression, lysosomal damage, and autophagosome clearance. Overexpression of SYT11 was found to rescue ATP13A2 and reduce autophagic dysfunction induced, suggesting that ATP13A2-mediated autophagy may be dependent on SYT11 function.

ATP13A2 Figure 1. Model proposed on how ATP13A2 and SYT11 establish a common network that regulates the autophagy–lysosomal pathway. (Bento, et al. 2016)

Kett et al. found that ATP13A2 is in the same region as LC3, a surface marker of autophagosomes, and may be a specific polycystic (MVB). This suggests that ATP13A2 may play an important role in the fusion of autophagosomes with MVB and lysosomal vesicles. An analysis of homozygous ATP13A2 mice revealed a phenotype of lysosomal storage disease (LSD). Recently, Sato et al. demonstrated that lysosomal dysfunction leads to accumulation of the mitochondrial ATP synthase subunit c. ATP13A2 knockout mice incubated by Schultheis et al., in which exons 12-15 and a portion of exon 16 were removed. The deleted exon includes a sequence encoding a catalytic phosphorylation site, which is critical for enzymatic activity.

References:

Fleming, S. M. (2017). Mechanisms of gene-environment interactions in parkinson’s disease. Current Environmental Health Reports, 4(2), 1-8.
Murphy, K. E., Cottle, L., Gysbers, A. M., Cooper, A. A., & Halliday, G. M. (2013). Atp13a2 (park9) protein levels are reduced in brain tissue of cases with lewy bodies. Acta Neuropathologica Communications, 1(1), 1-8.
Sato, S., Li, Y., & Hattori, N. (2017). Lysosomal defects in atp13a2 and gba associated familial parkinson’s disease. Journal of Neural Transmission, 124(11), 1395-1400.
Bento, C. F., Ashkenazi, A., Jimenezsanchez, M., & Rubinsztein, D. C. (2016). The parkinson’s disease-associated genes atp13a2 and syt11 regulate autophagy via a common pathway. Nature Communications, 7, 11803.
Kett, L. R., & Dauer, W. T. (2016). Endolysosomal dysfunction in parkinson's disease: recent developments and future challenges. Movement Disorders Official Journal of the Movement Disorder Society, 31(10), 1433-1443.
Schultheis, P. J., Fleming, S. M., Clippinger, A. K., Lewis, J., Tsunemi, T., & Giasson, B., et al. (2013). Atp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis, limited α-synuclein accumulation and age-dependent sensorimotor deficits. Human Molecular Genetics, 22(10), 2067-2082.

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