Kalvorakenteista myeliinin synteesi omaa tärkeän metabolisen piirinsä

MITEN ATP, GTP, CTP ja TTP ja UTP energiajärjestelmä    kohtaavat sen aluetta?

Aivokudos on  kaapeloitu myeliinillä. Neuronaalinen kudos  on erittäin  riippuvainen glukoosienergiasta ja hapen saannista.   Katson joitain asioita. On tärkeä saada  neuronaalisen  rakenteen  suojaava kalvojärjestelmä  pysymään  niin hyvässä kunnossa, että  lipidimodulin  uusiintuminen remodeling tapahtuu tasapainossa katabolian kanssa  puoliintumisajan   ollessa myös  aivorakenteen lipidimodulin osalta olemassa,  tosin ei niin  nopeana kuin esim maksan rakenteissa tapahtuva puoliintumisaika.

Ongelmataso:  https://pubmed.ncbi.nlm.nih.gov/?term=ataxins+and+proteosome

 

Myeliinistä artikkeli:

https://pubmed.ncbi.nlm.nih.gov/31766565/ 

 

. 2019 Nov 21;20(23):5854.

doi: 10.3390/ijms20235854.

In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Nesli-Ece Sen  ^{1   2} , Aleksandar Arsovic et al

Affiliations

• DOI: 10.3390/ijms20235854

Free PMC article

 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 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 (So) 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 (VLCFA-sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain  LCFAsphingomyelin. 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.

Keywords: SCA34; SCA38; Smpd1); acid sphingomyelinase (ASMase; amyotrophic lateral sclerosis (ALS); ceramide synthase (CERS2/CERS1); fatty acid elongase (Elovl1/4/5); leukodystrophy; neutral ceramidase (Asah2); neutral sphingomyelinase (Smpd3); olivo-ponto-cerebellar atrophy (OPCA); serine palmitoyltransferase 2 (Sptlc2).

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

MIKÄ GEENI?

ATXN2   Gene (12q24.12) Ataxin-2

NCBI Gene Summary for ATXN2 Gene

• This gene belongs to a group of genes that is associated with microsatellite-expansion diseases, a class of neurological and neuromuscular disorders caused by expansion of short stretches of repetitive DNA. The protein encoded by this gene has two globular domains near the N-terminus, one of which contains a clathrin-mediated trans-Golgi signal and an endoplasmic reticulum exit signal. The encoded cytoplasmic protein localizes to the endoplasmic reticulum and plasma membrane, is involved in endocytosis, and modulates mTOR signals, modifying ribosomal translation and mitochondrial function. The N-terminal region of the protein contains a polyglutamine tract of 14-31 residues that can be expanded in the pathogenic state to 32-200 residues. Intermediate length expansions of this tract increase susceptibility to amyotrophic lateral sclerosis, while long expansions of this tract result in spinocerebellar ataxia-2, an autosomal-dominantly inherited, neurodegenerative disorder. Genome-wide association studies indicate that loss-of-function mutations in this gene may be associated with susceptibility to type I diabetes, obesity and hypertension. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ATXN2 (Ataxin 2) is a Protein Coding gene. Diseases associated with ATXN2 include Spinocerebellar Ataxia 2 and Parkinson Disease, Late-Onset. Among its related pathways are Akt Signaling and Regulation of activated PAK-2p34 by proteasome mediated degradation. Gene Ontology (GO) annotations related to this gene include RNA binding and obsolete protein C-terminus binding. An important paralog of this gene is ATXN2L.

• GeneCards Symbol: ATXN2 ²
• Ataxin 2 ^{2 3 5}
• ATX2 ^{2 3 4 5}
• TNRC13 ^{3 4 5}
• SCA2 ^{3 4 5}

• Trinucleotide Repeat-Containing Gene 13 Protein ^{3 4}
• Spinocerebellar Ataxia Type 2 Protein ^{3 4}
• Ataxin-2 ^{3 4}
• Spinocerebellar Ataxia 2 (Olivopontocerebellar Ataxia 2, Autosomal Dominant, Ataxin 2) ²
• Trinucleotide Repeat Containing 13 ²

Protein attributes for ATXN2 Gene

Size:1313 amino acids. Molecular mass:140283 Da

Quaternary structure:

• Monomer (By similarity).
  Can also form homodimers (By similarity).
  Interacts with TARDBP; the interaction is RNA-dependent (PubMed:20740007).
  Interacts with RBFOX1 (PubMed:10814712).
  Interacts with polyribosomes (PubMed:16835262).
  Interacts with SH3GL2 and SH3GL3 (PubMed:18602463).
  Interacts with SH3KBP1 and CBL (By similarity).
  Interacts with EGFR (PubMed:18602463).
  Interacts with ATXN2L (PubMed:23209657)
  

  Molecular function for ATXN2 Gene according to UniProtKB/Swiss-Prot

  Function:Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane. ATX2_HUMAN,Q99700

  Molecular function for ATXN2 Gene according to GENATLAS

  Biochemistry:

  • ataxin 2,expressed in cytoplasms of specific neuronal groups with strong labeling of Purkinje cells ATXN2
  • trinucleotide repeat (CTG) containing 13 ATXN