Search for SCA2 blood RNA biomarkers highlights Ataxin-2 as strong modifier of the mitochondrial factor PINK1 levels.
Ataxin-2 (ATXN2) polyglutamine domain expansions of large size result in an autosomal dominantly inherited multi-system-atrophy of the nervous system named spinocerebellar ataxia type 2 (SCA2), while expansions of intermediate size act as polygenic risk factors for motor neuron disease (ALS and FTLD) and perhaps also for Levodopa-responsive Parkinson's disease (PD). In view of the established role of ATXN2 for RNA processing in periods of cell stress and the expression of ATXN2 in blood cells such as platelets, we investigated whether global deep RNA sequencing of whole blood from SCA2 patients identifies a molecular profile which might serve as diagnostic biomarker. The bioinformatic analysis of SCA2 blood global transcriptomics revealed various significant effects on RNA processing pathways, as well as the pathways of Huntington's disease and PD where mitochondrial dysfunction is crucial. Notably, an induction of PINK1 and PARK7 expression was observed. Conversely, expression of Pink1 was severely decreased upon global transcriptome profiling of Atxn2-knockout mouse cerebellum and liver, in parallel to strong effects on Opa1 and Ghitm, which encode known mitochondrial dynamics regulators. These results were validated by quantitative PCR and immunoblots. Starvation stress of human SH-SY5Y neuroblastoma cells led to a transcriptional phasic induction of ATXN2 in parallel to PINK1, and the knockdown of one enhanced the expression of the other during stress response. These findings suggest that ATXN2 may modify the known PINK1 roles for mitochondrial quality control and autophagy during cell stress. Given that PINK1 is responsible for autosomal recessive juvenile PD, this genetic interaction provides a concept how the degeneration of nigrostriatal dopaminergic neurons and the Parkinson phenotype may be triggered by ATXN2 mutations.
Experimental Neurology, Goethe University Medical School, 60590 Frankfurt/Main, Germany; Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory (NDAL), Boğaziçi University, 34342 Istanbul, Turkey.
Nesli Ece
NE
Sen
Experimental Neurology, Goethe University Medical School, 60590 Frankfurt/Main, Germany.
Jessica
J
Drost
Experimental Neurology, Goethe University Medical School, 60590 Frankfurt/Main, Germany.
Suzana
S
Gispert
Experimental Neurology, Goethe University Medical School, 60590 Frankfurt/Main, Germany.
Sylvia
S
Torres-Odio
Experimental Neurology, Goethe University Medical School, 60590 Frankfurt/Main, Germany.
Ewa
E
Damrath
Experimental Neurology, Goethe University Medical School, 60590 Frankfurt/Main, Germany.
Michael
M
Klinkenberg
Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory (NDAL), Boğaziçi University, 34342 Istanbul, Turkey.
Hamid
H
Hamzeiy
Department of Neurology, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey.
Gülden
G
Akdal
Department of Neurology, Faculty of Medicine, Izmir University, Izmir, Turkey.
Halil
H
Güllüoğlu
Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory (NDAL), Boğaziçi University, 34342 Istanbul, Turkey. Electronic address: basak@boun.edu.tr.
A Nazlı
AN
Başak
Experimental Neurology, Goethe University Medical School, 60590 Frankfurt/Main, Germany. Electronic address: auburger@em.uni-frankfurt.de.
Georg
G
Auburger
D000328:Adult; D000368:Aged; D000818:Animals; D000067698:Ataxin-2 / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D005192:Family Health; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009447:Neuroblastoma / Q000473:pathology; D010455:Peptides / Q000235:genetics*; D011494:Protein Kinases / Q000378:metabolism*; D020754:Spinocerebellar Ataxias / Q000097:blood* / Q000235:genetics; D014421:Turkey; D055815:Young Adult; D000099202:PTEN-Induced Putative Kinase
D000067698:Ataxin-2; D016895:Culture Media, Serum-Free; D020558:GTP Phosphohydrolases; D010455:Peptides; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C097188:polyglutamine; C415198:OPA1 protein, human
Autophagy; Mitochondrial dynamics; Neurodegeneration; Parkinsonism; RNA processing; Ribosomal translation