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Minor splicing pathway is not minor any more: Implications for the pathogenesis of motor neuron diseases
Author(s) -
Onodera Osamu,
Ishihara Tomohiko,
Shiga Atsushi,
Ariizumi Yuko,
Yokoseki Akio,
Nishizawa Masatoyo
Publication year - 2014
Publication title -
neuropathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.701
H-Index - 61
eISSN - 1440-1789
pISSN - 0919-6544
DOI - 10.1111/neup.12070
Subject(s) - spliceosome , rna splicing , snrnp , biology , small nuclear rna , microbiology and biotechnology , minor spliceosome , alternative splicing , cajal body , genetics , messenger rna , rna , gene , non coding rna
To explore the molecular pathogenesis of amyotrophic lateral sclerosis ( ALS ), the nuclear function of TAR‐DNA binding protein 43 kDa ( TDP ‐43) must be elucidated. TDP ‐43 is a nuclear protein that colocalizes with C ajal body or G em in cultured cells. Several recent studies have reported that the decreasing number of G ems accompanied the depletion of the causative genes for ALS , TDP ‐43 and FUS . Gems play an important role in the pathogenesis of spinal muscular atrophy. Gems are the sites of the maturation of spliceosomes, which are composed of uridylate‐rich ( U ) snRNAs (small nuclear RNAs ) and protein complex, small nuclear ribonuclearprotein ( snRNP ). Spliceosomes regulate the splicing of pre‐ mRNA and are classified into the major or minor classes, according to the consensus sequence of acceptor and donor sites of pre‐ mRNA splicing. Although the major class of spliceosomes regulates most pre‐ mRNA splicing, minor spliceosomes also play an important role in regulating the splicing or global speed of pre‐ mRNA processing. A mouse model of spinal muscular atrophy, in which the number of Gems is decreased, shows fewer subsets U snRNAs . Interestingly, in the central nervous system, U snRNAs belonging to the minor spliceosomes are markedly reduced. In ALS , the U 12 snRNA is decreased only in the tissue affected by ALS and not in other tissues. Although the molecular mechanisms underlying the decreased U12 snRNA resulting in cell dysfunction and cell death in motor neuron diseases remain unclear, these findings suggest that the disturbance of nuclear bodies and minor splicing may underlie the common molecular pathogenesis of motor neuron diseases.