A Blood-Derived Factor Rescues ALS: Platelet Factor 4 Activates OPTN-Dependent Autophagy to Clear SOD1 Aggregates Independently of PINK1.

Overview

1. Department of Rehabilitation Medicine, First Affiliated Hospital of Wenzhou Medical University and Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
2. Department of Rehabilitation Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, China
3. Chinese PLA General Hospital, Beijing, China
4. Department of Pediatrics, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
5. Department of Neurology and Neurological Laboratory of Hebei Province, The Second Hospital of Hebei Medical University, and Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, China
6. Department of Neurology, Peking University Third Hospital, Beijing, China

Abstract

Peripheral factors that systemically regulate amyotrophic lateral sclerosis (ALS) have remained elusive‐until now. Here, by integrating population‐scale epidemiology with mechanistic dissection, we identify platelet factor 4 (PF4) as the central driver of a circulating neuroprotective axis that restores proteostasis and rescues ALS. In a prospective cohort of >500 000 UK Biobank participants, platelet indices were strongly associated with ALS risk, and serum PF4 levels were significantly reduced in ALS patients. Systemic administration of recombinant PF4 in hSOD1G93A mice produced dramatic therapeutic effects: extended survival, preserved motor function, attenuated neuroinflammation, and reduced neuromuscular junction denervation. Remarkably, this efficacy appears pathology‐selective–robust in SOD1‐driven models but shows no observable effect in TDP‐43 or C9orf72 ALS models. Mechanistically, PF4 achieves what few molecules can: it engages the cell surface receptor LRP1 to activate the TBK1‐OPTN signaling axis, restoring impaired autophagic flux through a PINK1/Parkin‐independent pathway requiring ATG7, establishing a previously unrecognized peripheral platelet‐autophagy‐neuron axis that facilitates the co‐clearance of pathological SOD1 aggregates and damaged mitochondria. This study unveils PF4 as a first‐in‐class circulating autophagy regulator with therapeutic potential in ALS. Beyond identifying a candidate biomarker and drug lead, it reveals that systemic factors can directly engage central proteostatic machinery–opening a new frontier for ALS therapy.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• data.mendeley.com/preview/xx2jzy64hp — at Mendeley Data; found in “Data Availability Statement”
• geo:GSE158264 — at NCBI GEO; found in the text, “PF4 Induces Global Transcriptional…”

Data Availability Statement

The processed RNA‐seq data (including quantification matrices) supporting the findings of this study have been deposited in Mendeley Data for peer review purposes (https://data.mendeley.com/preview/xx2jzy64hp?a=64e82365‐fcc7‐45aa‐a025‐738a3e7b4068 (https://data.mendeley.com/preview/xx2jzy64hp?a=64e82365-fcc7-45aa-a025-738a3e7b4068)). The raw sequencing data have been deposited in the NCBI Gene Expression Omnibus (GEO) under the accession number GSE338930 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE338930). UK Biobank data: This research has been conducted using the UK Biobank Resource under Application Number [108832]. The data are available from the UK Biobank (http://www.ukbiobank.ac.uk/) upon successful registration and application. Microscopy and Western blot data: All original western blot images, microscopy data, and other supporting data reported in this paper will be shared by the lead contact upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, pages, dates, 13 authors, 6 keywords, 2 funders, 71 references.

Cite

This paper

Xie, Q., Zhu, Y., Jiang, W., Xie, H., Li, Y., Hu, M., Li, K., Yu, H., Pan, Y., Jiang, C., Song, X., Fan, D., & Deng, B. (2026). A Blood-Derived Factor Rescues ALS: Platelet Factor 4 Activates OPTN-Dependent Autophagy to Clear SOD1 Aggregates Independently of PINK1. Advanced science (Weinheim, Baden-Wurttemberg, Germany), e76778. https://doi.org/10.1002/advs.76778

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