Dysregulated dopamine storage increases the vulnerability to alpha-synuclein in nigral neurons

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Standard

Dysregulated dopamine storage increases the vulnerability to alpha-synuclein in nigral neurons. / Ulusoy, Ayse; Björklund, Tomas; Buck, Kerstin; Kirik, Deniz.

I: Neurobiology of Disease, Vol. 47, Nr. 3, 2012, s. 367-377.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

APA

CBE

MLA

Vancouver

Author

RIS

TY - JOUR

T1 - Dysregulated dopamine storage increases the vulnerability to alpha-synuclein in nigral neurons

AU - Ulusoy, Ayse

AU - Björklund, Tomas

AU - Buck, Kerstin

AU - Kirik, Deniz

PY - 2012

Y1 - 2012

N2 - Impairments in the capacity of dopaminergic neurons to handle cytoplasmic dopamine may be a critical factor underlying the selective vulnerability of midbrain dopamine neurons in Parkinson's disease. Furthermore, toxicity of alpha-synuclein in dopaminergic neurons has been suggested to be mediated by direct interaction between dopamine and alpha-synuclein through formation of abnormal alpha-synuclein species, although direct in vivo evidence to support this hypothesis is lacking. Here, we investigated the role of dopamine availability on alpha-synuclein mediated neurodegeneration in vivo. We found that overexpression of alpha-synuclein in nigral dopamine neurons in mice with deficient vesicular storage of dopamine led to a significant increase in dopaminergic neurodegeneration. Importantly, silencing the tyrosine hydroxylase enzyme - thereby reducing dopamine content in the nigral neurons - reversed the increased vulnerability back to the baseline level observed in wild-type littermates, but failed to eliminate it completely. Importantly, TH knockdown was not effective in altering the toxicity in the wild-type animals. Taken together, our data suggest that under normal circumstances, in healthy dopamine neurons, cytoplasmic dopamine is tightly controlled such that it does not contribute significantly to alpha-synuclein mediated toxicity. Dysregulation of the dopamine machinery in the substantia nigra, on the other hand, could act as a trigger for induction of increased toxicity in these neurons and could explain how these neurons become more vulnerable and die in the disease process. (C) 2012 Elsevier Inc. All rights reserved.

AB - Impairments in the capacity of dopaminergic neurons to handle cytoplasmic dopamine may be a critical factor underlying the selective vulnerability of midbrain dopamine neurons in Parkinson's disease. Furthermore, toxicity of alpha-synuclein in dopaminergic neurons has been suggested to be mediated by direct interaction between dopamine and alpha-synuclein through formation of abnormal alpha-synuclein species, although direct in vivo evidence to support this hypothesis is lacking. Here, we investigated the role of dopamine availability on alpha-synuclein mediated neurodegeneration in vivo. We found that overexpression of alpha-synuclein in nigral dopamine neurons in mice with deficient vesicular storage of dopamine led to a significant increase in dopaminergic neurodegeneration. Importantly, silencing the tyrosine hydroxylase enzyme - thereby reducing dopamine content in the nigral neurons - reversed the increased vulnerability back to the baseline level observed in wild-type littermates, but failed to eliminate it completely. Importantly, TH knockdown was not effective in altering the toxicity in the wild-type animals. Taken together, our data suggest that under normal circumstances, in healthy dopamine neurons, cytoplasmic dopamine is tightly controlled such that it does not contribute significantly to alpha-synuclein mediated toxicity. Dysregulation of the dopamine machinery in the substantia nigra, on the other hand, could act as a trigger for induction of increased toxicity in these neurons and could explain how these neurons become more vulnerable and die in the disease process. (C) 2012 Elsevier Inc. All rights reserved.

KW - Short hairpin RNA

KW - Tyrosine hydroxylase

KW - Adeno-associated virus

KW - VMAT2

KW - Transgenic mice

U2 - 10.1016/j.nbd.2012.05.012

DO - 10.1016/j.nbd.2012.05.012

M3 - Article

VL - 47

SP - 367

EP - 377

JO - Neurobiology of Disease

T2 - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

IS - 3

ER -