Friday, July 26, 2013

smallRNA in neurodegenerative diseases

Basic question: how does the small RNA function in neurodegenerative disease brain?

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.
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.

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:

DiseaseMain clinical featuresCausal repeat (gene)Repeat locationMechanism or categoryComments
DM1Muscle weakness, myotonia, cardiac-endocrine-GI disease, MRCTG (DM1, also known as DMPK)3′ UTRRNA GOFA very common form of muscular dystrophy
DM2Muscle weakness, myotonia, cardiac-endocrine-GI diseaseCTG (ZNF9, also known as CNBP)IntronRNA GOFA striking phenocopy of DM1
DRPLASeizures, choreoathetosis, ataxia, cognitive declineCAG (ATN1)Coding regionPolyglutamine GOFVery rare, most patients are in Japan
FMR1MR, facial dysmorphism, autismCGG (FMR1)5′ UTRHypermethylation of promoter, LOFMost common inherited MR
FMR2MR, hyperactivityGCC (FMR2)5′ UTRLOFNeeds to be ruled out in X-linked MR
FRDAAtaxia, sensory loss, weakness, diabetes mellitus, cardiomyopathyGAA (FXN)IntronLOF, phenocopy of mitochondrial diseaseMost common inherited ataxia in Caucasian ethnicity
FXTASAtaxia, intention tremor, parkinsonismCGG (FMR1)5′ UTRRNA GOFPremutation carriers only
HDChorea, dystonia, cognitive decline, psychiatric diseaseCAG (HTT)Coding regionPolyglutamine GOFOne of the most common inherited diseases in humans
HDL2Chorea, dystonia, cognitive declineCTG (JPH3)3′ UTR, coding regionRNA GOF, poly-amino acid GOF and/or LOF?A striking phenocopy of HD
Myoclonic epilepsy of Unverricht and LundborgPhotosensitive myoclonus, tonic–clonic seizures, cerebellar degenerationCCCCGCCCCGCG (CSTB)PromoterLOFRare autosomal recessive disorder found in Finland and N. Africa
OPMDEyelid weakness, dysphagia, proximal limb weaknessGCG (PABPN1)Coding regionPolyalanine GOFModest expansion causes disease
SBMAProximal limb weakness, lower motor neuron diseaseCAG (AR)Coding regionPolyglutamine GOFPhenotype includes LOF androgen insensitivity
SCA1Ataxia, dysarthria, spasticity, ophthalmoplegiaCAG (ATXN1)Coding regionPolyglutamine GOFAccounts for 6% of all dominant ataxia
SCA2Ataxia, slow eye movement, hyporeflexia, motor disease, occasional parkinsonismCAG (ATXN2)Coding regionPolyglutamine GOFATXN2 protein may not reside in the nucleus
SCA3Ataxia, dystonia, lower motor neuron diseaseCAG (ATXN3)Coding regionPolyglutamine GOFMost common dominant ataxia
SCA6Ataxia, dysarthria, sensory loss, occasionally episodicCAG (CACNA1A)Coding regionPolyglutamine GOFCausal gene encodes a subunit of a P/Q-type Ca2+ channel
SCA7Ataxia, dysarthria, cone-rod dystrophy retinal diseaseCAG (ATXN7)Coding regionPolyglutamine GOFClinically distinct as patients have retinal disease
SCA8Ataxia, dysarthria, nystagmus, spasticityCTG/CAG (ATXN8)Untranslated RNA, coding regionRNA GOF and polyglutamine GOFMany cases of reduced penetrance
SCA10Ataxia, dysarthria, seizures, dysphagiaATTCT (ATXN10)IntronRNA GOF?Huge repeats; only Mexican ancestry?
SCA12Tremor, ataxia, spasticity, dementiaCAG (PPP2R2B)Promoter, 5′ UTR?UnknownCausal gene encodes a phosphatase
SCA17Ataxia, dementia, chorea, seizures, dystoniaCAG (TBP)Coding regionPolyglutamine GOFCausal gene encodes a common transcription factor (TBP)
Syndromic/non-syndromic X-linked mental retardationMR alone, with seizures or with dysarthria and dystoniaGCG (ARX)Coding regionProbably LOFAssociated 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_synonym="CDR; CDR34; CDR62A"
                     /note="Derived by automated computational analysis using
                     gene prediction method: BestRefseq."
                     /product="cerebellar degeneration-related antigen 1"

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