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ATXN2 in Health and Disease
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ATXN2 in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2020)

Special Issue Editor

Prof. Dr. Georg Auburger

E-Mail Website
Guest Editor
Experimental Neurology, Goethe University Medical Faculty, 60590 Frankfurt am Main, Germany
Interests: genetic mechanisms of neurodegeneration, in particular ATXN2 and PINK1

Special Issue Information

Dear Colleagues,

Ataxin-2 (ATXN2) and its homologues down to yeast and plants have been implicated in RNA binding, in translation regulation, and in EGF/insulin receptor endocytosis. They act during stress responses, relocalizing to cytosolic stress granules and modulating RNA decay in P-bodies. Defense against viral, bacterial, and possibly toxic mitochondrial RNA seems to be a part of their roles. Downstream of AMP kinase, they act to repress mTORC1 signals that govern cell growth.

Their genetic variants trigger various pathological consequences:

  • Large expansion causes autosomal dominant Spinocerebellar ataxia type 2;
  • Intermediate expansion increases risk for amyotrophic lateral sclerosis/frontotemporal dementia;
  • Single nucleotide polymorphisms associated with diabetes mellitus, hypertension, and life until 100 years;
  • Their depletion in mice triggers obesity with dyslipidemia and insulin resistance;
  • Their depletion in flies protects from other spinocerebellar ataxias and tauopathies;
  • Their mutations alter fertility;
  • Their depletion in yeast rescues the lethality of poly(A)-binding-protein deficiency.

In view of the dramatic neuroprotective effects of ATXN2 depletion, clinical trials will use antisense oligonucleotides and locked nucleic acids to prevent disease. Now there is an urgent need to define the natural course of the ATXN2-associated disorders, to identify biomarkers of ATXN2 effects, to understand their pathway roles, and to elucidate potential side-effects of ATXN2 deficiency.

The journal mainly focuses on molecular mechanisms or pathophysiology implications including basic studies in biochemistry, molecular biology, and molecular medicine.

Prof. Dr. Georg Auburger
Guest Editor

Manuscript Submission Information

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Keywords

  • neurodegeneration
  • neuroprotection
  • ASO
  • LNA
  • dsRNA
  • RNP granules
  • nucleocytoplasmic shuttling
  • metabolic excess versus atrophy

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Published Papers (5 papers)

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Research

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18 pages, 3550 KiB  
Article
The ATXN2 Orthologs CID3 and CID4, Act Redundantly to In-Fluence Developmental Pathways throughout the Life Cycle of Arabidopsis thaliana
by Zaira M. López-Juárez, Laura Aguilar-Henonin and Plinio Guzmán
Int. J. Mol. Sci. 2021, 22(6), 3068; https://doi.org/10.3390/ijms22063068 - 17 Mar 2021
Cited by 2 | Viewed by 2866
Abstract
RNA-binding proteins (RBPs) are key elements involved in post-transcriptional regulation. Ataxin-2 (ATXN2) is an evolutionarily conserved RBP protein, whose function has been studied in several model organisms, from Saccharomyces cerevisiae to the Homo sapiens. ATXN2 interacts with poly(A) binding proteins (PABP) and [...] Read more.
RNA-binding proteins (RBPs) are key elements involved in post-transcriptional regulation. Ataxin-2 (ATXN2) is an evolutionarily conserved RBP protein, whose function has been studied in several model organisms, from Saccharomyces cerevisiae to the Homo sapiens. ATXN2 interacts with poly(A) binding proteins (PABP) and binds to specific sequences at the 3′UTR of target mRNAs to stabilize them. CTC-Interacting Domain3 (CID3) and CID4 are two ATXN2 orthologs present in plant genomes whose function is unknown. In the present study, phenotypical and transcriptome profiling were used to examine the role of CID3 and CID4 in Arabidopsis thaliana. We found that they act redundantly to influence pathways throughout the life cycle. cid3cid4 double mutant showed a delay in flowering time and a reduced rosette size. Transcriptome profiling revealed that key factors that promote floral transition and floral meristem identity were downregulated in cid3cid4 whereas the flowering repressor FLOWERING LOCUS C (FLC) was upregulated. Expression of key factors in the photoperiodic regulation of flowering and circadian clock pathways, were also altered in cid3cid4, as well as the expression of several transcription factors and miRNAs encoding genes involved in leaf growth dynamics. These findings reveal that ATXN2 orthologs may have a role in developmental pathways throughout the life cycle of plants. Full article
(This article belongs to the Special Issue ATXN2 in Health and Disease)
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24 pages, 2666 KiB  
Article
Mid-Gestation lethality of Atxn2l-Ablated Mice
by Jana Key, Patrick N. Harter, Nesli-Ece Sen, Elise Gradhand, Georg Auburger and Suzana Gispert
Int. J. Mol. Sci. 2020, 21(14), 5124; https://doi.org/10.3390/ijms21145124 - 20 Jul 2020
Cited by 14 | Viewed by 3902
Abstract
Depletion of yeast/fly Ataxin-2 rescues TDP-43 overexpression toxicity. In mouse models of Amyotrophic Lateral Sclerosis via TDP-43 overexpression, depletion of its ortholog ATXN2 mitigated motor neuron degeneration and extended lifespan from 25 days to >300 days. There is another ortholog in mammals, named [...] Read more.
Depletion of yeast/fly Ataxin-2 rescues TDP-43 overexpression toxicity. In mouse models of Amyotrophic Lateral Sclerosis via TDP-43 overexpression, depletion of its ortholog ATXN2 mitigated motor neuron degeneration and extended lifespan from 25 days to >300 days. There is another ortholog in mammals, named ATXN2L (Ataxin-2-like), which is almost uncharacterized but also functions in RNA surveillance at stress granules. We generated mice with Crispr/Cas9-mediated deletion of Atxn2l exons 5-8, studying homozygotes prenatally and heterozygotes during aging. Our novel findings indicate that ATXN2L absence triggers mid-gestational embryonic lethality, affecting female animals more strongly. Weight and development stages of homozygous mutants were reduced. Placenta phenotypes were not apparent, but brain histology showed lamination defects and apoptosis. Aged heterozygotes showed no locomotor deficits or weight loss over 12 months. Null mutants in vivo displayed compensatory efforts to maximize Atxn2l expression, which were prevented upon nutrient abundance in vitro. Mouse embryonal fibroblast cells revealed more multinucleated giant cells upon ATXN2L deficiency. In addition, in human neural cells, transcript levels of ATXN2L were induced upon starvation and glucose and amino acids exposure, but this induction was partially prevented by serum or low cholesterol administration. Neither ATXN2L depletion triggered dysregulation of ATXN2, nor a converse effect was observed. Overall, this essential role of ATXN2L for embryogenesis raises questions about its role in neurodegenerative diseases and neuroprotective therapies. Full article
(This article belongs to the Special Issue ATXN2 in Health and Disease)
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20 pages, 4376 KiB  
Article
The RNA-Binding Protein ATXN2 is Expressed during Megakaryopoiesis and May Control Timing of Gene Expression
by Marten Hansen, Sabrina Zeddies, Marjolein Meinders, Franca di Summa, Ewa Rollmann, Floris P.J. van Alphen, Arjan J. Hoogendijk, Kat S. Moore, Melanie Halbach, Laura Gutiérrez, Maartje van den Biggelaar, Daphne C. Thijssen-Timmer, Georg W.J. Auburger, Emile van den Akker and Marieke von Lindern
Int. J. Mol. Sci. 2020, 21(3), 967; https://doi.org/10.3390/ijms21030967 - 31 Jan 2020
Cited by 8 | Viewed by 4206
Abstract
Megakaryopoiesis is the process during which megakaryoblasts differentiate to polyploid megakaryocytes that can subsequently shed thousands of platelets in the circulation. Megakaryocytes accumulate mRNA during their maturation, which is required for the correct spatio-temporal production of cytoskeletal proteins, membranes and platelet-specific granules, and [...] Read more.
Megakaryopoiesis is the process during which megakaryoblasts differentiate to polyploid megakaryocytes that can subsequently shed thousands of platelets in the circulation. Megakaryocytes accumulate mRNA during their maturation, which is required for the correct spatio-temporal production of cytoskeletal proteins, membranes and platelet-specific granules, and for the subsequent shedding of thousands of platelets per cell. Gene expression profiling identified the RNA binding protein ATAXIN2 (ATXN2) as a putative novel regulator of megakaryopoiesis. ATXN2 expression is high in CD34+/CD41+ megakaryoblasts and sharply decreases upon maturation to megakaryocytes. ATXN2 associates with DDX6 suggesting that it may mediate repression of mRNA translation during early megakaryopoiesis. Comparative transcriptome and proteome analysis on megakaryoid cells (MEG-01) with differential ATXN2 expression identified ATXN2 dependent gene expression of mRNA and protein involved in processes linked to hemostasis. Mice deficient for Atxn2 did not display differences in bleeding times, but the expression of key surface receptors on platelets, such as ITGB3 (carries the CD61 antigen) and CD31 (PECAM1), was deregulated and platelet aggregation upon specific triggers was reduced. Full article
(This article belongs to the Special Issue ATXN2 in Health and Disease)
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28 pages, 5085 KiB  
Article
In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism
by Nesli-Ece Sen, Aleksandar Arsovic, David Meierhofer, Susanne Brodesser, Carola Oberschmidt, Júlia Canet-Pons, Zeynep-Ece Kaya, Melanie-Vanessa Halbach, Suzana Gispert, Konrad Sandhoff and Georg Auburger
Int. J. Mol. Sci. 2019, 20(23), 5854; https://doi.org/10.3390/ijms20235854 - 21 Nov 2019
Cited by 20 | Viewed by 6369
Abstract
Ataxin-2 (human gene symbol ATXN2) acts during stress responses, modulating mRNA translation and nutrient metabolism. Ataxin-2 knockout mice exhibit progressive obesity, dyslipidemia, and insulin resistance. Conversely, the progressive ATXN2 gain of function due to the fact of polyglutamine (polyQ) expansions leads to [...] Read more.
Ataxin-2 (human gene symbol ATXN2) acts during stress responses, modulating mRNA translation and nutrient metabolism. Ataxin-2 knockout mice exhibit progressive obesity, dyslipidemia, and insulin resistance. Conversely, the progressive ATXN2 gain of function due to the fact of polyglutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2) with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-Knockin (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin, and gangliosides GM1a/GD1b despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide–sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage and not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals; thus, our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode, and mouse orthologs as mTORC1 inhibitors and autophagy promoters. Full article
(This article belongs to the Special Issue ATXN2 in Health and Disease)
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Review

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14 pages, 4737 KiB  
Review
Neuroimaging Biomarkers in SCA2 Gene Carriers
by Mario Mascalchi and Alessandra Vella
Int. J. Mol. Sci. 2020, 21(3), 1020; https://doi.org/10.3390/ijms21031020 - 4 Feb 2020
Cited by 10 | Viewed by 3512
Abstract
A variety of Magnetic Resonance (MR) and nuclear medicine (NM) techniques have been used in symptomatic and presymptomatic SCA2 gene carriers to explore, in vivo, the physiopathological biomarkers of the neurological dysfunctions characterizing the associated progressive disease that presents with a cerebellar syndrome, [...] Read more.
A variety of Magnetic Resonance (MR) and nuclear medicine (NM) techniques have been used in symptomatic and presymptomatic SCA2 gene carriers to explore, in vivo, the physiopathological biomarkers of the neurological dysfunctions characterizing the associated progressive disease that presents with a cerebellar syndrome, or less frequently, with a levodopa-responsive parkinsonian syndrome. Morphometry performed on T1-weighted images and diffusion MR imaging enable structural and microstructural evaluation of the brain in presymptomatic and symptomatic SCA2 gene carriers, in whom they show the typical pattern of olivopontocerebellar atrophy observed at neuropathological examination. Proton MR spectroscopy reveals, in the pons and cerebellum of SCA2 gene carriers, a more pronounced degree of abnormal neurochemical profile compared to other spinocerebellar ataxias with decreased NAA/Cr and Cho/Cr, increased mi/Cr ratios, and decreased NAA and increased mI concentrations. These neurochemical abnormalities are detectable also in presymtomatic gene carriers. Resting state functional MRI (rsfMRI) demonstrates decreased functional connectivity within the cerebellum and of the cerebellum with fronto-parietal cortices and basal ganglia in symptomatic SCA2 subjects. 18F-fluorodeoxyglucose Positron Emission Tomography (PET) shows a symmetric decrease of the glucose uptake in the cerebellar cortex, the dentate nucleus, the brainstem and the parahippocampal cortex. Single photon emission tomography and PET using several radiotracers have revealed almost symmetric nigrostriatal dopaminergic dysfunction irrespective of clinical signs of parkinsonism which are already present in presymtomatic gene carriers. Longitudinal small size studies have proven that morphometry and diffusion MR imaging can track neurodegeneration in SCA2, and hence serve as progression biomarkers. So far, such a capability has not been reported for proton MR spectroscopy, rsfMRI and NM techniques. A search for the best surrogate marker for future clinical trials represents the current challenge for the neuroimaging community. Full article
(This article belongs to the Special Issue ATXN2 in Health and Disease)
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