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

초록

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.

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