It's been shown that small RNAs (miRNA, piRNA, circular RNA) present in the brain. Recent researches even show that piRNA and circular RNA also expressed highly in brain tissues.
Rajasethupathy P, Antonov I, Sheridan R, Frey S, Sander C, Tuschl T, Kandel ER.
Cell. 2012 Apr 27;149(3):693-707. doi: 10.1016/j.cell.2012.02.057.
The authors found several piRNA clusters highly expressed in Aplysia CNS, with the biogenesis pattern of piRNA in germline, including 5' U, piwi protein loaded, clustered, nuclear localized, sensitive to serotonin. They found that "the Piwi/piRNA complex facilitates serotonin-dependent methylation of a conserved CpG island in the promoter of CREB2, the major inhibitory constraint of memory in Aplysia, leading to enhanced long-term synaptic facilitation". They speculated that the piwi/piRNA complex methylates the promoter of target gene (CREB2 in this case) by first accessing its nascent transcript. Not sure if this also happened to other neuron-functioning genes, such as HES4 and HTT for HD.
Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J.Cell. 2012 Apr 27;149(3):693-707. doi: 10.1016/j.cell.2012.02.057.
Nature. 2013 Mar 21;495(7441):384-8. doi: 10.1038/nature11993. Epub 2013 Feb 27.
Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, Loewer A, Ziebold U, Landthaler M, Kocks C, le Noble F, Rajewsky N.
Nature. 2013 Mar 21;495(7441):333-8. doi: 10.1038/nature11928. Epub 2013 Feb 27.
In these two new studies, the primary circular RNA of interest is an antisense transcript to CDR1 termed CDR1as (CDR1 antisense, used herein) or ciRS-7 (circular RNA sponge for miR-7). This RNA was validated by rigorous bioinformatic and molecular studies. Seventy-four copies of a miR-7 binding site are present in this circular RNA owing to the presence of a tandem repeat in the transcribed sequence of CDR1as. These binding sites are conserved across eutherian (placental) mammals, whereas the intervening sequences generally are not.
(Cite: http://www.nature.com/mt/journal/v21/n6/full/mt2013101a.html)
It's interesting that the circular RNA discovered this year also anti-sense to the target/host gene. Would that be a general mechanism that neurodegenerative disease are controlled by the anti-sense RNA?
Another question: why the repeated peptide/trinucleotide insertion or expansion is a common feature for most neurodegenerative disease?
Here is the table for the at least 20 inherit neuro-diseases and the associated repeat insertion:
Ref: http://www.nature.com/nrg/journal/v11/n4/fig_tab/nrg2748_T1.html
Not only genes in the list, other genes like the CDR1 (Cerebellar Degeneration-Related) gene mentioned above also contains several hexapeptide repeats.
Nature. 2013 Mar 21;495(7441):333-8. doi: 10.1038/nature11928. Epub 2013 Feb 27.
In these two new studies, the primary circular RNA of interest is an antisense transcript to CDR1 termed CDR1as (CDR1 antisense, used herein) or ciRS-7 (circular RNA sponge for miR-7). This RNA was validated by rigorous bioinformatic and molecular studies. Seventy-four copies of a miR-7 binding site are present in this circular RNA owing to the presence of a tandem repeat in the transcribed sequence of CDR1as. These binding sites are conserved across eutherian (placental) mammals, whereas the intervening sequences generally are not.
(Cite: http://www.nature.com/mt/journal/v21/n6/full/mt2013101a.html)
It's interesting that the circular RNA discovered this year also anti-sense to the target/host gene. Would that be a general mechanism that neurodegenerative disease are controlled by the anti-sense RNA?
Another question: why the repeated peptide/trinucleotide insertion or expansion is a common feature for most neurodegenerative disease?
Here is the table for the at least 20 inherit neuro-diseases and the associated repeat insertion:
| Disease | Main clinical features | Causal repeat (gene) | Repeat location | Mechanism or category | Comments |
|---|---|---|---|---|---|
| DM1 | Muscle weakness, myotonia, cardiac-endocrine-GI disease, MR | CTG (DM1, also known as DMPK) | 3′ UTR | RNA GOF | A very common form of muscular dystrophy |
| DM2 | Muscle weakness, myotonia, cardiac-endocrine-GI disease | CTG (ZNF9, also known as CNBP) | Intron | RNA GOF | A striking phenocopy of DM1 |
| DRPLA | Seizures, choreoathetosis, ataxia, cognitive decline | CAG (ATN1) | Coding region | Polyglutamine GOF | Very rare, most patients are in Japan |
| FMR1 | MR, facial dysmorphism, autism | CGG (FMR1) | 5′ UTR | Hypermethylation of promoter, LOF | Most common inherited MR |
| FMR2 | MR, hyperactivity | GCC (FMR2) | 5′ UTR | LOF | Needs to be ruled out in X-linked MR |
| FRDA | Ataxia, sensory loss, weakness, diabetes mellitus, cardiomyopathy | GAA (FXN) | Intron | LOF, phenocopy of mitochondrial disease | Most common inherited ataxia in Caucasian ethnicity |
| FXTAS | Ataxia, intention tremor, parkinsonism | CGG (FMR1) | 5′ UTR | RNA GOF | Premutation carriers only |
| HD | Chorea, dystonia, cognitive decline, psychiatric disease | CAG (HTT) | Coding region | Polyglutamine GOF | One of the most common inherited diseases in humans |
| HDL2 | Chorea, dystonia, cognitive decline | CTG (JPH3) | 3′ UTR, coding region | RNA GOF, poly-amino acid GOF and/or LOF? | A striking phenocopy of HD |
| Myoclonic epilepsy of Unverricht and Lundborg | Photosensitive myoclonus, tonic–clonic seizures, cerebellar degeneration | CCCCGCCCCGCG (CSTB) | Promoter | LOF | Rare autosomal recessive disorder found in Finland and N. Africa |
| OPMD | Eyelid weakness, dysphagia, proximal limb weakness | GCG (PABPN1) | Coding region | Polyalanine GOF | Modest expansion causes disease |
| SBMA | Proximal limb weakness, lower motor neuron disease | CAG (AR) | Coding region | Polyglutamine GOF | Phenotype includes LOF androgen insensitivity |
| SCA1 | Ataxia, dysarthria, spasticity, ophthalmoplegia | CAG (ATXN1) | Coding region | Polyglutamine GOF | Accounts for 6% of all dominant ataxia |
| SCA2 | Ataxia, slow eye movement, hyporeflexia, motor disease, occasional parkinsonism | CAG (ATXN2) | Coding region | Polyglutamine GOF | ATXN2 protein may not reside in the nucleus |
| SCA3 | Ataxia, dystonia, lower motor neuron disease | CAG (ATXN3) | Coding region | Polyglutamine GOF | Most common dominant ataxia |
| SCA6 | Ataxia, dysarthria, sensory loss, occasionally episodic | CAG (CACNA1A) | Coding region | Polyglutamine GOF | Causal gene encodes a subunit of a P/Q-type Ca2+ channel |
| SCA7 | Ataxia, dysarthria, cone-rod dystrophy retinal disease | CAG (ATXN7) | Coding region | Polyglutamine GOF | Clinically distinct as patients have retinal disease |
| SCA8 | Ataxia, dysarthria, nystagmus, spasticity | CTG/CAG (ATXN8) | Untranslated RNA, coding region | RNA GOF and polyglutamine GOF | Many cases of reduced penetrance |
| SCA10 | Ataxia, dysarthria, seizures, dysphagia | ATTCT (ATXN10) | Intron | RNA GOF? | Huge repeats; only Mexican ancestry? |
| SCA12 | Tremor, ataxia, spasticity, dementia | CAG (PPP2R2B) | Promoter, 5′ UTR? | Unknown | Causal gene encodes a phosphatase |
| SCA17 | Ataxia, dementia, chorea, seizures, dystonia | CAG (TBP) | Coding region | Polyglutamine GOF | Causal gene encodes a common transcription factor (TBP) |
| Syndromic/non-syndromic X-linked mental retardation | MR alone, with seizures or with dysarthria and dystonia | GCG (ARX) | Coding region | Probably LOF | Associated with West syndrome or Partington syndrome |
| AR, androgen receptor; ARX, aristaless-related homeobox; ATN1, atrophin 1; ATXN, ataxin; CACNA1A, voltage-dependent P/Q-type calcium channel subunit α-1A; CSTB, cystatin B; DM, myotonic dystrophy; DMPK, DRPLA, dentatorubral-pallidoluysian atrophy; FMR1, fragile X mental retardation syndrome; FMR2, fragile X E mental retardation; FRDA, Friedreich's ataxia; FXN, frataxin; FXTAS, fragile X tremor ataxia syndrome; GI, gastrointestinal; GOF, gain of function; HD, Huntington's disease; HDL2, Huntington's disease-like 2; HTT, huntingtin; JPH3, junctophilin 3; LOF, loss of function; MR, mental retardation; OPMD, oculopharyngeal muscular dystrophy; PABPN1, poly(A)-binding protein, nuclear 1; PPP2R2B, protein phosphatase 2 regulatory subunit B, β isoform; SBMA, spinal and bulbar muscular atrophy; SCA, spinocerebellar ataxia; TBP, TATA box-binding protein; ZNF9, zinc finger 9. | |||||
Not only genes in the list, other genes like the CDR1 (Cerebellar Degeneration-Related) gene mentioned above also contains several hexapeptide repeats.
CDS 387..1175
/gene="CDR1"
/gene_synonym="CDR; CDR34; CDR62A"
/note="Derived by automated computational analysis using
gene prediction method: BestRefseq."
/codon_start=1
/product="cerebellar degeneration-related antigen 1"
/protein_id="NP_004056.2"
/db_xref="GI:44889483"
/db_xref="CCDS:CCDS14670.1"
/db_xref="GeneID:1038"
/db_xref="HGNC:1798"
/db_xref="HPRD:02361"
/db_xref="MIM:302650"
/translation="MAWLEDVDFLEDVPLLEDIPLLEDVPLLEDVPLLEDTSRLEDIN
LMEDMALLEDVDLLEDTDFLEDLDFSEAMDLREDKDFLEDMDSLEDMALLEDVDLLED
TDFLEDPDFLEAIDLREDKDFLEDMDSLEDLEAIGRCGFSGRHGFFGRRRFSGRPKLS
GRLGLLGRRGFSGRLGGYWKTWIFWKTWIFWKTWIFRKTYIGWKTWIFSGRCGLTGRP
GFGGRRRFFWKTLTDWKTWISFWKTLIDWKTWISFWKTLIDWKI"
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