Enhancing heme synthesis attenuates pathological α-synuclein propagation in vivo

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Intraneuronal alpha-synuclein (αS) accumulation drives Parkinson's disease and dementia with Lewy bodies.
• αS pathology spreads via seed-dependent propagation, but effective therapies are lacking.
• Porphyrins inhibit αS aggregation but have poor blood-brain barrier (BBB) penetration.

Purpose of the Study:

• To investigate if 5-aminolevulinic acid (5-ALA), a heme precursor, modulates αS accumulation and propagation.
• To explore the role of intracellular heme in αS propagation.
• To assess the therapeutic potential of 5-ALA in vivo.

Main Methods:

• In vitro assessment of 5-ALA's effect on αS seeding.
• Treatment of primary mouse neurons with 5-ALA to measure heme synthesis and αS aggregation.
• In vivo study involving intrastriatal injection of αS fibrils in mice, followed by oral 5-ALA administration.
• Biochemical and immunohistochemical analyses to quantify αS propagation and pathology.

Main Results:

• 5-ALA treatment enhanced intracellular heme synthesis in neurons.
• 5-ALA suppressed seed-dependent αS aggregation in vitro.
• Oral 5-ALA administration significantly reduced αS propagation to the contralateral hemisphere in mice.
• 5-ALA treatment markedly decreased phosphorylated αS pathology in key brain regions.

Conclusions:

• Oral 5-ALA administration effectively suppresses αS propagation in vivo.
• Enhanced intracellular heme synthesis is a potential mechanism underlying 5-ALA's therapeutic effect.
• Modulating the heme biosynthetic pathway offers a novel therapeutic strategy for synucleinopathies like Parkinson's disease.