Therapeutic targeting of blood-derived protein infiltration to modulate neuroinflammation in cerebellar ataxia

Neuroinflammation is one of the key drivers of spinocerebellar ataxia type 2 (SCA2), yet the role of prothrombin-derived proteins in its pathogenesis remains unclear. Here, we show that prothrombin-derived proteins, thrombin and prothrombin kringle-2 (pKr-2), are elevated in the plasma of patients with cerebellar ataxia (CA) and in the cerebellum of SCA2 mice. Intervention strategies, reinforcing the blood–brain barrier (BBB) with caffeine administration and inhibiting thrombin/pKr-2 production through oral administration of rivaroxaban, attenuated cerebellar infiltration of prothrombin-derived proteins, neuroinflammation, and motor deficits in SCA2 mice, whereas pKr-2 upregulation exacerbated neuronal damage and behavioral impairments. These findings reveal a distinct peripheral proteomic signature linked to a cerebellar pathogenic pathway and suggest that limiting the entry of prothrombin-derived proteins into the cerebellum may represent a critical therapeutic approach in CA.