The usual suspects, dopamine and alpha-synuclein, conspire to cause neurodegeneration.
Mov Disord
; 34(2): 167-179, 2019 02.
Article
in En
| MEDLINE
| ID: mdl-30633814
ABSTRACT
Parkinson's disease (PD) is primarily a movement disorder driven by the loss of dopamine-producing neurons in the substantia nigra (SN). Early identification of the oxidative properties of dopamine implicated it as a potential source of oxidative stress in PD, yet few studies have investigated dopamine neurotoxicity in vivo. The discovery of PD-causing mutations in α-synuclein and the presence of aggregated α-synuclein in the hallmark Lewy body pathology of PD revealed another important player. Despite extensive efforts, the precise role of α-synuclein aggregation in neurodegeneration remains unclear. We recently manipulated both dopamine levels and α-synuclein expression in aged mice and found that only the combination of these 2 factors caused progressive neurodegeneration of the SN and an associated motor deficit. Dopamine modified α-synuclein aggregation in the SN, resulting in greater abundance of α-synuclein oligomers and unique dopamine-induced oligomeric conformations. Furthermore, disruption of the dopamine-α-synuclein interaction rescued dopaminergic neurons from degeneration in transgenic Caenorhabditis elegans models. In this Perspective, we discuss these findings in the context of known α-synuclein and dopamine biology, review the evidence for α-synuclein oligomer toxicity and potential mechanisms, and discuss therapeutic implications. © 2019 International Parkinson and Movement Disorder Society.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Dopamine
/
Alpha-Synuclein
/
Nerve Degeneration
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Mov Disord
Journal subject:
NEUROLOGIA
Year:
2019
Document type:
Article
Affiliation country:
Estados Unidos