Parkinson patient fibroblasts show increased alpha-synuclein expression.
Parkinson's disease (PD) is a neurodegenerative movement disorder of advanced age with largely unknown etiology, but well documented tissue damage from oxidative stress. Increased alpha-synuclein (SNCA) expression is known to cause a rare form of PD, early-onset autosomal dominant PARK4. We have previously shown that loss-of-function mutations of the mitochondrial kinase PINK1 which cause the early-onset recessive PARK6 variant result in oxidative damage in patient fibroblasts. We now investigated the molecular chain of events from mitochondrial dysfunction to cell death which is largely unknown. Primary skin fibroblast cultures from patients were analysed for gene expression anomalies. In G309D-PINK1 patient fibroblasts, mainly genes regulated by oxidative stress, as well as genes encoding synaptic proteins such as SNCA showed altered expression. The induction of SNCA was also observed in control fibroblasts with knock-down of PINK1. The induction of SNCA expression was found to constitute a specific disease biomarker in sporadic PD patient fibroblasts. To understand the mechanism of this induction, we exposed control fibroblasts to oxidative, proteasomal and endoplasmic reticulum stress and were able to trigger the SNCA expression upregulation. Our data indicate that loss-of-function of PINK1 leads to enhanced alpha-synuclein expression and altered cell-cell contact. Alpha-synuclein induction might represent a common event for different variants of PD as well as a PD-specific trigger of neurodegeneration. We propose that the expression changes described might potentially serve as biomarkers that allow objective PD patient diagnosis in an accessible, peripheral tissue.
Department of Neurology, University Medical School, Frankfurt am Main, Germany.
Hans-Hermann
HH
Hoepken
Suzana
S
Gispert
Mekhman
M
Azizov
Michael
M
Klinkenberg
Filomena
F
Ricciardi
Alexander
A
Kurz
Blas
B
Morales-Gordo
Michael
M
Bonin
Olaf
O
Riess
Thomas
T
Gasser
Donat
D
Kögel
Helmuth
H
Steinmetz
Georg
G
Auburger
D000368:Aged; D001224:Aspartic Acid / Q000235:genetics; D002478:Cells, Cultured; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000473:pathology; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology*; D011494:Protein Kinases / Q000235:genetics; D013997:Time Factors; D051844:alpha-Synuclein / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D001224:Aspartic Acid; D005998:Glycine; D011494:Protein Kinases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase