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Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death
Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A, Meaney DF, Trojanowski JQ et al.. Neuron, 2011-10-01
Topic: Brain proteins, microglia and lab models
Inclusions composed of α-synuclein (α-syn), i.e., Lewy bodies (LBs) and Lewy neurites (LNs), define synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Here, we demonstrate that preformed fibrils generated from full-length and truncated recombinant α-syn enter primary neurons, probably by adsorptive-mediated endocytosis, and promote recruitment of soluble endogenous α-syn into insoluble PD-like LBs and LNs. Remarkably, endogenous α-syn was sufficient for formation of these aggregates, and overexpression of wild-type or mutant α-syn was not required. LN-like pathology first developed in axons and propagated to form LB-like inclusions in perikarya. Accumulation of pathologic α-syn led to selective decreases in synaptic proteins, progressive impairments in neuronal excitability and connectivity, and, eventually, neuron death. Thus, our data contribute important insights into the etiology and pathogenesis of PD-like α-syn inclusions and their impact on neuronal functions, and they provide a model for discovering therapeutics targeting pathologic α-syn-mediated neurodegeneration.
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APA 7th
Volpicelli-Daley, L. A., Luk, K. C., Patel, T. P., Tanik, S. A., Riddle, D. M., Stieber, A., et al. (2011). Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. https://doi.org/10.1016/j.neuron.2011.08.033
Vancouver
Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A, et al. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011. doi:10.1016/j.neuron.2011.08.033. PMID: 21982369.
BibTeX
@article{volpicellidaley2011-21982369,
author = {Volpicelli-Daley, L. A. and Luk, K. C. and Patel, T. P. and Tanik, S. A. and Riddle, D. M. and Stieber, A. and Meaney, D. F. and Trojanowski, J. Q. and others},
title = {{Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death}},
journal = {Neuron},
year = {2011},
doi = {10.1016/j.neuron.2011.08.033},
pmid = {21982369},
url = {https://doi.org/10.1016/j.neuron.2011.08.033}
}
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Key findings
- Here, we demonstrate that preformed fibrils generated from full-length and truncated recombinant α-syn enter primary neurons, probably by adsorptive-mediated endocytosis, and promote recruitment of soluble endogenous α-syn into insoluble PD-like LBs and LNs.
- Remarkably, endogenous α-syn was sufficient for formation of these aggregates, and overexpression of wild-type or mutant α-syn was not required.
- LN-like pathology first developed in axons and propagated to form LB-like inclusions in perikarya.
- Accumulation of pathologic α-syn led to selective decreases in synaptic proteins, progressive impairments in neuronal excitability and connectivity, and, eventually, neuron death.
- Thus, our data contribute important insights into the etiology and pathogenesis of PD-like α-syn inclusions and their impact on neuronal functions, and they provide a model for discovering therapeutics targeting pathologic α-syn-mediated neurodegeneration.
Why it matters
In cultured primary neurons, lab-made alpha-synuclein fibrils entered the cells and pulled the neurons' own alpha-synuclein into clumps resembling the Lewy bodies and Lewy neurites seen in Parkinson's disease and dementia with Lewy bodies. The clumps formed without adding extra alpha-synuclein, appeared first in axons and then in the cell body, and were followed by loss of synaptic proteins, worsening nerve-cell signalling and connectivity, and eventually cell death. This is a cell-culture model the authors offer for testing future therapies. It is not a treatment, and it did not study Alzheimer's disease or people.
Study details
- Evidence strengthLow
How this study scored 56/100
Published in a peer-reviewed 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 | 7 / 10 | Tier 3 — peer-reviewed journal (Neuron) |
| Journal's citation record | 4 / 4 | Neuron: journal h-index 689 (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 | 2011 — 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 | 7 / 7 | Cited 1,573 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 92.5 citations a year over 17 year(s) since 2011 |
| Impact for its field and year | 6 / 6 | Cited 41.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 26 other studies in this library |
| Still being cited | 4 / 4 | Cited 329 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Virginia M.‐Y. Lee: h-index 202 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Pennsylvania: institution h-index 1,859 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 21982369) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 56 / 100 | — |
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