Evidence map›Paper›PMID 41646404›Full record

ArticleResearch square2026

Quantifying the Acute Toxicity of Alpha-Synuclein Membrane-Accumulation in a Cell-Based Assay.

Baoyi Li, Amirah K Anderson, Oren A Levy, Nagendran Ramalingam, Ulf Dettmer

Abstract readPreprint
In one paragraph

Article in Research square, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

5 authors.

Baoyi LiWycombe Abbey.
Amirah K AndersonBrigham and Women's Hospital and Harvard Medical School.
Oren A LevyColumbia University Irving Medical Center.
Nagendran RamalingamBrigham and Women's Hospital and Harvard Medical School.
Ulf DettmerBrigham and Women's Hospital and Harvard Medical School.

Funding

Elucidating the Biological Differences Between Distinct Fibrillar and Non-Fibrillar Alpha-Synuclein Inclusions in Human Stem-Cell ModelsR01NS109209 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI KHURANA, VIKRAM · 2020 to 2024
$4.5M
How Serine-129 Phosphorylation Status Affects the Spreading of α-Synuclein Pathology in Vivo: a Study in Knock-in AnimalsRF1NS133979 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI DETTMER, ULF, RAMALINGAM, NAGENDRAN · 2023 to 2023
$2.2M
Polo-like-kinase-2-dependent α-Synuclein Serine-129 Phosphorylation: a Physiological RoleDuring Synaptic ActivityRF1NS122880 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI DETTMER, ULF, RAMALINGAM, NAGENDRAN · 2022 to 2022
$2.1M
Stabilizing native α-synuclein homeostasis to prevent insoluble α-synuclein aggregatesR01NS099328 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI DETTMER, ULF · 2017 to 2021
$1.9M
Polo-like-kinase-2-dependent α-Synuclein Serine-129 Phosphorylation: a Physiological RoleDuring Synaptic ActivityR01NS122880 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI Ulf Dettmer, Nagendran Ramalingam · 2025 to 2026
$1.4M
How Serine-129 Phosphorylation Status Affects the Spreading of α-Synuclein Pathology in Vivo: a Study in Knock-in AnimalsR01NS133979 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI Ulf Dettmer, Nagendran Ramalingam · 2026 to 2026
$724k
Contrasting pathomechanisms of membrane versus cytosol alpha-synuclein excessR21NS121826 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI DETTMER, ULF · 2021 to 2021
$505k
Distinguishing α-Synuclein S129 Phosphorylation in Health and Lewy Body DementiaR21AG085401 · NIA · UNIVERSITY OF SOUTH FLORIDA · PI Nagendran Ramalingam · 2024 to 2026
$433k
NIA NIH HHS R21 AG085401NINDS NIH HHS R01 NS099328NINDS NIH HHS R01 NS109209NINDS NIH HHS R01 NS122880NINDS NIH HHS R01 NS133979NINDS NIH HHS R21 NS121826NINDS NIH HHS RF1 NS122880NINDS NIH HHS RF1 NS133979
6 · The paper itself

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects over 12 million people worldwide. A central pathological feature is the accumulation of aggregated alpha-synuclein (αS) in Lewy bodies and Lewy neurites. Engineered αS variants such as 3K (E35K + E46K + E61K) and KLK (KTKEGV→KLKEGV in 6 repeats) have been shown to enhance membrane binding and aggregation propensity, contributing to cellular toxicity. To further investigate the impact of 3K and KLK on αS biology, we developed a sensitive assay in a human neuroblastoma model to assess expression levels and cytotoxicity. Relative to wild-type αS, the 3K mutant exhibited reduced steady-state expression and increased toxicity, consistent with prior reports. In contrast, the KLK mutant showed no marked change in protein expression but induced significantly higher toxicity, more than the 3K variant. These findings underscore the utility of our assay in dissecting disease-relevant mechanisms and highlight the potential of engineered αS variants to model pathogenic features of PD. This platform offers a versatile tool for evaluating therapeutic strategies targeting αS aggregation and toxicity in PD and related synucleinopathies.

Indexed as

alpha-synucleincellular assayParkinson’s diseasesynucleinopathy

Identifiers

PMID41646404
PMCPMC12869599

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.