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Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity
Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, Caldwell KA, Caldwell GA et al.. Nature genetics, 2009-02-01
Topic: Brain proteins, microglia and lab models
Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, collectively referred to as synucleinopathies, are associated with a diverse group of genetic and environmental susceptibilities. The best studied of these is PD. alpha-Synuclein (alpha-syn) has a key role in the pathogenesis of both familial and sporadic PD, but evidence linking it to other predisposition factors is limited. Here we report a strong genetic interaction between alpha-syn and the yeast ortholog of the PD-linked gene ATP13A2 (also known as PARK9). Dopaminergic neuron loss caused by alpha-syn overexpression in animal and neuronal PD models is rescued by coexpression of PARK9. Further, knockdown of the ATP13A2 ortholog in Caenorhabditis elegans enhances alpha-syn misfolding. These data provide a direct functional connection between alpha-syn and another PD susceptibility locus. Manganese exposure is an environmental risk factor linked to PD and PD-like syndromes. We discovered that yeast PARK9 helps to protect cells from manganese toxicity, revealing a connection between PD genetics (alpha-syn and PARK9) and an environmental risk factor (PARK9 and manganese). Finally, we show that additional genes from our yeast screen, with diverse functions, are potent modifiers of alpha-syn-induced neuron loss in animals, establishing a diverse, highly conserved interaction network for alpha-syn.
Key findings
- Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, collectively referred to as synucleinopathies, are associated with a diverse group of genetic and environmental susceptibilities.
Why it matters
In yeast, roundworms and other lab models, this study found that the Parkinson's-linked gene PARK9 (ATP13A2) interacts with alpha-synuclein: adding PARK9 "rescued" alpha-synuclein-driven loss of dopamine neurons, and reducing it in worms "enhances alpha-syn misfolding." In yeast, PARK9 also helped protect cells from manganese toxicity, which the authors present as a link between Parkinson's genes and an environmental risk factor. These are early model-system results about Parkinson's and related synucleinopathies, not human evidence and not a treatment, cure or prevention for Alzheimer's disease.
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Study details
- Evidence strengthLow
How this study scored 54/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Nature genetics) |
| Journal's citation record | 4 / 4 | Nature Genetics: journal h-index 776 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2009 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 536 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 28.2 citations a year over 19 year(s) since 2009 |
| Impact for its field and year | 5 / 6 | Cited 30.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 6 other studies in this library |
| Still being cited | 2 / 4 | Cited 36 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Susan Lee Lindquist: h-index 142 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Howard Hughes Medical Institute: institution h-index 2,008 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 19182805) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 54 / 100 | — |
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APA 7th
Gitler, A. D., Chesi, A., Geddie, M. L., Strathearn, K. E., Hamamichi, S., Hill, K. J., et al. (2009). Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nature genetics. https://doi.org/10.1038/ng.300
Vancouver
Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, et al. Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nature genetics. 2009. doi:10.1038/ng.300. PMID: 19182805.
BibTeX
@article{gitler2009-19182805,
author = {Gitler, A. D. and Chesi, A. and Geddie, M. L. and Strathearn, K. E. and Hamamichi, S. and Hill, K. J. and Caldwell, K. A. and Caldwell, G. A. and others},
title = {{Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity}},
journal = {Nature genetics},
year = {2009},
doi = {10.1038/ng.300},
pmid = {19182805},
url = {https://doi.org/10.1038/ng.300}
}
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