A comprehensive genetic study of the proteasomal subunit S6 ATPase in German Parkinson's disease patients.
Dysfunction of proteasomal protein degradation is involved in neurodegeneration in Parkinson's disease (PD). Recently we identified the regulatory proteasomal subunit S6 ATPase as a novel interactor of synphilin-1, which is a substrate of the ubiquitin-ligase Parkin (PARK2) and an interacting protein of alpha-synuclein (PARK1). To further investigate a potential role in the pathogenesis of PD, we performed a detailed mutation analysis of the S6 ATPase gene in a large sample of 486 German sporadic and familial PD patients. Direct sequencing revealed two novel intronic variants. An insertion/deletion variant in intron 5 of the S6 ATPase gene was more frequent in patients compared to controls. Moreover, this variant was significantly more frequent in early-onset compared to late-onset PD patients. The identification of a genetic link between a regulatory proteasomal subunit and PD further underscores the relevance of disturbed protein degradation in PD.
Wahl
Claudia
C
Laboratory of Functional Neurogenomics, Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tubingen, Germany.
Kautzmann
Sabine
S
Krebiehl
Guido
G
Strauss
Karsten
K
Woitalla
Dirk
D
Müller
Thomas
T
Bauer
Peter
P
Riess
Olaf
O
Krüger
Rejko
R
D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000368:Aged; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D010300:Parkinson Disease / Q000453:epidemiology* / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D011489:Protein Denaturation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002352:Carrier Proteins; D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C118958:SNCAIP protein, human; C088863:PSMC4 protein, human; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities