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 (CNS) contributes to disease progression via seed-dependent propagation. Currently, there are no disease-modifying drugs for these disorders. 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 the present study, we investigated the effect of 5-ALA on 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 that increased intracellular heme levels inhibit 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 four weeks. Biochemical analysis 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 5-ALA-treated groups. Collectively, these findings indicate that enhancement of intracellular heme synthesis by oral 5-ALA administration suppresses αS propagation in vivo . Increasing intracellular heme levels may therefore represent a novel therapeutic strategy for neurodegenerative synucleinopathies.