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

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 hSOD1^G93A 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.