Dataset Information

Human Friedreich's Ataxia model proteomics

ABSTRACT: Friedreich’s ataxia (FA) is a multisystem neurodegenerative disorder marked by early-onset sensory neuropathy and cardiomyopathy. However, the molecular determinants of tissue-specific vulnerability remain poorly understood. Here, we establish a human dual-cell model of FA by differentiating sensory neurons and cardiomyocytes from the same patients, enabling parallel molecular profiling of disease-relevant cell types. Proteomic analysis reveals distinct, cell-type-specific pathway disruptions in response to frataxin deficiency, reflecting divergent susceptibilities to mitochondrial dysfunction. Leveraging this platform, we investigate Miro1 Reducer 3 (MR3), a selective chemical probe targeting Miro1, a mitochondrial outer membrane GTPase implicated in redox regulation in FA. MR3 treatment modulates molecular signatures in a cell-type-dependent manner, enhancing pathways related to cardiac contractility in cardiomyocytes and synaptic function and cell-cell communication in sensory neurons. Mechanistically, MR3 reduces mitochondrial reactive oxygen species and restores membrane potential in FA sensory neurons via potential allosteric reshaping of Miro1 protein. To expand the chemical diversity of this scaffold, we conducted ligand-based virtual screening of over 3 billion compounds and identified multiple new Miro1 ligands with improved neuroprotective activity. These findings underscore the power of matched, patient-derived cell model in decoding cell-type-specific disease mechanisms and therapeutic responses, and highlight Miro1-targeted modulation as a promising therapeutic strategy in FA.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Stem Cell, Fibroblast

SUBMITTER: Sujyoti Chandra

LAB HEAD: Xinan Wang

PROVIDER: PXD070711 | Pride | 2026-06-15

REPOSITORIES: Pride

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			Action	DRS
	20230602_Wang_SChandra_12949_1_HC5_Fibroblast.raw	Raw
	20230602_Wang_SChandra_12949_2_FA5_Fibroblast.raw	Raw
	20230905_WangX_SChandra_13394_1_HC5_1_Fibroblast.raw	Raw
	20230905_WangX_SChandra_13394_2_FA5_Fibroblast.raw	Raw
	20230905_WangX_SChandra_13394_3_HC5__1_Fibroblast.raw	Raw

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Publications

Chemical modulation of Miro1 alleviates cell-type-specific vulnerabilities in Friedreich's ataxia.

Chandra Sujyoti S Kwak Chulhwan S CS Du Zehui Z Barisano Giuseppe G Nguyen Kong T KT Vinogradov Vlad V Wang Xinnan X

Cell chemical biology 20260608

Friedreich's ataxia (FA) is marked by early-onset sensory neurodegeneration and cardiomyopathy. We establish a human dual-cell model of FA by differentiating sensory neurons and cardiomyocytes from the same patients, enabling parallel molecular profiling of disease-relevant cell types. Proteomic analysis reveals distinct, cell-type-specific pathway disruptions in response to frataxin deficiency. Leveraging this platform, we investigate Miro1 reducer 3 (MR3), a selective chemical probe binding Mi ...[more]

PMID: 42259290

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