Enhancing heme synthesis attenuates pathological α-synuclein propagation in vivo

Intraneuronal α-synuclein (αS) accumulation is a central event in the pathogenesis of Parkinson's disease and dementia with Lewy bodies. The spread of αS pathology throughout the central nervous system contributes to disease progression via seed-dependent propagation, yet disease-modifying therapies remain unavailable. We previously reported that porphyrin compounds inhibit αS aggregation in vitro; however, because of their high molecular weight, porphyrins poorly penetrate the blood-brain barrier (BBB). Heme, a porphyrin derivative, is synthesized from 5-aminolevulinic acid (5-ALA) via the heme biosynthetic pathway. In this study, we investigated whether 5-ALA modulates αS accumulation and propagation. Although porphyrin compounds inhibited αS seeding in vitro, 5-ALA itself did not. However, treatment of mouse primary neurons with 5-ALA enhanced heme synthesis and suppressed seed-dependent αS aggregation, suggesting a potential role for intracellular heme in modulating αS propagation. We further evaluated the effects of 5-ALA in an in vivo αS propagation model. Preformed αS fibrils were unilaterally injected into the striatum of wild-type mice, followed by oral administration of 5-ALA at three doses (0, 1.7, and 20 mg/kg/day) for 4 weeks. Biochemical analyses demonstrated that 5-ALA significantly reduced the propagation of sarkosyl-insoluble αS to the contralateral hemisphere. Immunohistochemical analyses revealed a marked reduction in phosphorylated αS pathology in the amygdala and substantia nigra in the 5-ALA-treated groups. Collectively, these findings indicate that oral administration of 5-ALA suppresses αS propagation in vivo, potentially through enhancement of intracellular heme synthesis. Modulation of the heme biosynthetic pathway may represent a novel therapeutic strategy for synucleinopathies.