Evidence map›Paper›PMID 38906862›Full record

ArticleNPJ Parkinson's disease2024

Enhancing mitochondrial proteolysis alleviates alpha-synuclein-mediated cellular toxicity.

Xi Zhang, Linhao Ruan, Hu Wang, Jin Zhu, Taibo Li, Gordon Sun, Yi Dong, Yuhao Wang, Gil Berreby, Ashley Shay and 5 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in NPJ Parkinson's disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing 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

11 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors.

Xi ZhangCenter for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Linhao RuanCenter for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Hu WangNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Jin ZhuMechanobiology Institute, National University of Singapore, Singapore, 117411, Singapore.
Taibo LiDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21218, USA.
Gordon SunCenter for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Yi DongCenter for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Yuhao WangCenter for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Gil BerrebyCenter for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Ashley ShayCenter for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0009-0001-0184-3910
Rong ChenNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Sreekumar RamachandranCenter for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Valina L DawsonDiana Helis Henry Medical Research Foundation, New Orleans, LA, 70130-2685, USA.ORCID http://orcid.org/0000-0002-2915-3970
Ted M DawsonDiana Helis Henry Medical Research Foundation, New Orleans, LA, 70130-2685, USA.ORCID http://orcid.org/0000-0002-6459-0893
Rong LiCenter for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. rong@jhu.edu.

Funding

Cellular dynamics in division, motility and evolutionary adaptationR35GM118172 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI LI, RONG · 2016 to 2019
$2.8M
LSM880 Laser-scanning Microscope with Airyscan ModuleS10OD023548 · OD · JOHNS HOPKINS UNIVERSITY · PI KUO, SCOT CHARLES · 2018 to 2018
$439k
Diana Helis Henry Medical Research Foundation H-2017NIGMS NIH HHS R35 GM118172NIH HHS S10 OD023548
6 · The paper itself

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing protein aggregates known as Lewy bodies (LB). Here, we investigated the entry of α-Syn into mitochondria to cause mitochondrial dysfunction and loss of cellular fitness in vivo. We show that α-Syn expressed in yeast and human cells is constitutively imported into mitochondria. In a transgenic mouse model, the level of endogenous α-Syn accumulation in mitochondria of dopaminergic neurons and microglia increases with age. The imported α-Syn is degraded by conserved mitochondrial proteases, most notably NLN and PITRM1 (Prd1 and Cym1 in yeast, respectively). α-Syn in the mitochondrial matrix that is not degraded interacts with respiratory chain complexes, leading to loss of mitochondrial DNA (mtDNA), mitochondrial membrane potential and cellular fitness decline. Importantly, enhancing mitochondrial proteolysis by increasing levels of specific proteases alleviated these defects in yeast, human cells, and a PD model of mouse primary neurons. Together, our results provide a direct link between α-synuclein-mediated cellular toxicity and its import into mitochondria and reveal potential therapeutic targets for the treatment of α-synucleinopathies.

Identifiers

PMID38906862
PMCPMC11192938

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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.