SCA8 mRNA expression suggests an antisense regulation of KLHL1 and correlates to SCA8 pathology.
An increasing number of inherited neurodegenerative diseases are known to be caused by the expansion of unstable trinucleotide repeat tracts. Spinocerebellar ataxia type 8 (SCA8) has been identified as being partly caused by a CTG expansion in an untranslated, endogenous antisense RNA that overlaps the Kelch-like 1 (KLHL1) gene. Clinically, SCA8 patients show similar features to those with the other SCAs, including limb and truncal ataxia, ataxic dysarthria and horizontal nystagmus, all of which are signs of dysfunction of the cerebellar system. However, allele sizes within the SCA8 proposed pathogenic range have been reported in patients with ataxia of unknown etiology, in individuals from pedigrees with other SCA or Friedreich's ataxia, and in patients with Alzheimer's disease, schizophrenia or parkinsonism. These observations suggest that mutation of the SCA8 locus might affect neurons other than the cerebellum. Antisense transcripts are known to regulate complementary sense transcripts and are involved in several biologic functions, such as development, adaptive response, and viral infection. In order to test whether SCA8 affects the KLHL1 expression by antisense RNA in brain cells, we examined the expression pattern of KLHL1 and SCA8 in human tissues and in mouse brain regions. SCA8 expression was colocalized with KLHL1 transcript in many brain regions whose functions are correlated to the clinical symptoms of SCA8 patients. These findings lead to the hypothesis of a possible relevance that SCA8 transcript downregulates KLHL1 expression through an antisense mechanism, which then leads to SCA8 neuropathogenesis.
Chen
Wei-Lun
WL
Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan.
Lin
Jun-Wei
JW
Huang
Hei-Jen
HJ
Wang
Su-Min
SM
Su
Ming-Tsan
MT
Lee-Chen
Guey-Jen
GJ
Chen
Chiung-Mei
CM
Hsieh-Li
Hsiu Mei
HM
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism; D011467:Prostate / Q000378:metabolism; D062085:RNA, Long Noncoding; D012333:RNA, Messenger / Q000032:analysis; D022661:RNA, Untranslated; D020754:Spinocerebellar Ataxias / Q000378:metabolism*; D013737:Testis / Q000378:metabolism*; D013788:Thalamus / Q000378:metabolism; D014018:Tissue Distribution
C415906:ATXN8OS gene product, human; C514889:KLHL1 protein, mouse; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D022661:RNA, Untranslated; C533578:SCA8 protein, mouse