Acquired dysregulation of dopamine homeostasis reproduces features of Parkinson's disease
The catecholamine neurotransmitter dopamine has the potential to act as an endogenous neurotoxin when its vesicular sequestration is dysregulated. Despite postmortem analyses from patients with Parkinson's disease that demonstrate decreased vesicular sequestration of dopamine with a corresponding increase in dopamine metabolism, dopamine's contribution to nigrostriatal dopaminergic degeneration in Parkinson's disease has been debated. Here, we present a new in vivo model demonstrating the induction of Parkinson's disease-associated pathogenic mechanisms of degeneration resulting from acquired dysregulation of dopamine sequestration in nigrostriatal dopaminergic neurons in adult rats. Utilizing adeno-associated virus (serotype 2), viral-mediated small-hairpin RNA interference of endogenous vesicular monoamine transporter 2 (VMAT2) expression resulted in a loss of VMAT2 protein expression in transduced dopaminergic cell bodies in the substantia nigra with a corresponding loss of VMAT2 protein within the striatal terminals. The loss of VMAT2 resulted in an accumulation of cytosolic dopamine and subsequent increased dopamine metabolism, deficits in dopamine-mediated behaviors, and degeneration of nigrostriatal dopaminergic neurons that was rescued through reintroduction of exogenous VMAT2, demonstrating that the toxicity was specific to the loss of VMAT2. Analysis of parkinsonian pathogenic mechanisms of degeneration identified oxidative damage, activation of Parkinson's disease-associated kinase LRRK2, and the formation of aberrant α-synuclein. This model demonstrates that a progressive acquired loss of VMAT2 expression in adulthood is sufficient to induce Parkinson's disease-associated pathogenic mechanisms of degeneration and provides a new model to further investigate the consequences of cytosolic dopamine.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:6 |
|---|---|
| Enthalten in: |
NPJ Parkinson's disease - 6(2020), 1 vom: 13. Nov., Seite 34 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Bucher, Meghan L [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Revised 30.06.2021 published: Electronic Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1038/s41531-020-00134-x |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM318643863 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM318643863 | ||
| 003 | DE-627 | ||
| 005 | 20231225165801.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41531-020-00134-x |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1062.xml |
| 035 | |a (DE-627)NLM318643863 | ||
| 035 | |a (NLM)33298952 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Bucher, Meghan L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Acquired dysregulation of dopamine homeostasis reproduces features of Parkinson's disease |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 30.06.2021 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a The catecholamine neurotransmitter dopamine has the potential to act as an endogenous neurotoxin when its vesicular sequestration is dysregulated. Despite postmortem analyses from patients with Parkinson's disease that demonstrate decreased vesicular sequestration of dopamine with a corresponding increase in dopamine metabolism, dopamine's contribution to nigrostriatal dopaminergic degeneration in Parkinson's disease has been debated. Here, we present a new in vivo model demonstrating the induction of Parkinson's disease-associated pathogenic mechanisms of degeneration resulting from acquired dysregulation of dopamine sequestration in nigrostriatal dopaminergic neurons in adult rats. Utilizing adeno-associated virus (serotype 2), viral-mediated small-hairpin RNA interference of endogenous vesicular monoamine transporter 2 (VMAT2) expression resulted in a loss of VMAT2 protein expression in transduced dopaminergic cell bodies in the substantia nigra with a corresponding loss of VMAT2 protein within the striatal terminals. The loss of VMAT2 resulted in an accumulation of cytosolic dopamine and subsequent increased dopamine metabolism, deficits in dopamine-mediated behaviors, and degeneration of nigrostriatal dopaminergic neurons that was rescued through reintroduction of exogenous VMAT2, demonstrating that the toxicity was specific to the loss of VMAT2. Analysis of parkinsonian pathogenic mechanisms of degeneration identified oxidative damage, activation of Parkinson's disease-associated kinase LRRK2, and the formation of aberrant α-synuclein. This model demonstrates that a progressive acquired loss of VMAT2 expression in adulthood is sufficient to induce Parkinson's disease-associated pathogenic mechanisms of degeneration and provides a new model to further investigate the consequences of cytosolic dopamine | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Barrett, Caitlyn W |e verfasserin |4 aut | |
| 700 | 1 | |a Moon, Connor J |e verfasserin |4 aut | |
| 700 | 1 | |a Mortimer, Amanda D |e verfasserin |4 aut | |
| 700 | 1 | |a Burton, Edward A |e verfasserin |4 aut | |
| 700 | 1 | |a Greenamyre, J Timothy |e verfasserin |4 aut | |
| 700 | 1 | |a Hastings, Teresa G |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t NPJ Parkinson's disease |d 2015 |g 6(2020), 1 vom: 13. Nov., Seite 34 |w (DE-627)NLM259702250 |x 2373-8057 |7 nnns |
| 773 | 1 | 8 | |g volume:6 |g year:2020 |g number:1 |g day:13 |g month:11 |g pages:34 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41531-020-00134-x |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 6 |j 2020 |e 1 |b 13 |c 11 |h 34 | ||