ALOX15 (Arachidonate 15-Lipoxygenase) encodes a member of the lipoxygenase family of enzymes that catalyze the oxidation of polyunsaturated fatty acids, particularly arachidonic acid, to produce bioactive lipid mediators including 15-hydroxyeicosatetraenoic acid (15-HETE) and lipoxins. This gene plays important roles in lipid metabolism, inflammatory responses, and cellular signaling, with emerging relevance to neurodegenerative diseases. [1]
ALOX15 catalyzes the peroxidation of arachonic acid and other polyunsaturated fatty acids at position 15, producing 15(S)-hydroperoxyeicosatetraenoic acid (15(S)-HPETE), which can be further reduced to 15(S)-HETE or converted to lipoxins. The enzyme contains a non-heme iron center essential for its catalytic activity and requires iron for proper folding and function. [2]
ALOX15 is expressed in various tissues including: [3]
In the brain, ALOX15 expression is particularly notable in glial cells, where it contributes to lipid signaling and inflammatory responses. [4]
Key pathways involving ALOX15 include: [5]
ALOX15 has been implicated in Alzheimer's disease pathogenesis through multiple mechanisms:
Amyloid metabolism: 15-HETE can influence amyloid precursor protein (APP) processing and amyloid-beta (Aβ) production. Studies have shown altered ALOX15 expression in AD brain tissue, particularly in regions affected by neurodegeneration.
Neuroinflammation: As a key enzyme in lipid mediator production, ALOX15 contributes to the neuroinflammatory environment in AD. The balance between pro-inflammatory eicosanoids and anti-inflammatory lipoxins is disrupted in AD brains.
Neuronal lipid signaling: ALOX15-derived lipid mediators regulate neuronal survival, synaptic plasticity, and cognitive function. Dysregulation of this pathway may contribute to cognitive decline.
In Parkinson's disease, ALOX15 involvement includes:
Dopaminergic neuron survival: 15-HETE signaling affects the viability of dopaminergic neurons in the substantia nigra. Altered ALOX15 expression has been observed in PD brain tissue.
Neuroinflammation: Microglial ALOX15 contributes to neuroinflammation through production of pro-inflammatory lipid mediators, potentially accelerating dopaminergic neuron loss.
Alpha-synuclein aggregation: Lipid metabolism alterations may influence alpha-synuclein aggregation and Lewy body formation.
Emerging evidence links ALOX15 to ALS:
Motor neuron inflammation: ALOX15 expression is elevated in ALS spinal cord tissue, particularly in microglia and astrocytes surrounding motor neurons.
Eicosanoid imbalance: Altered lipid mediator production may contribute to motor neuron degeneration and inflammatory processes in ALS.
ALOX15 represents a potential therapeutic target for neurodegenerative diseases:
ALOX15 expression levels and activity in cerebrospinal fluid (CSF) or peripheral blood mononuclear cells may serve as:
Key PubMed references on ALOX15 in neurodegeneration:
Chinnici et al. The role of 15-lipoxygenase in neuroinflammation and Alzheimer's disease, J Neuroinflammation (2021). 2021. ↩︎
Joshi et al. 15-Lipoxygenase regulates amyloid precursor protein processing and amyloid-β metabolism, Neurobiol Aging (2019). 2019. ↩︎
Zhang et al. ALOX15 deficiency protects against MPTP-induced parkinsonism through regulation of microglial activation, Cell Mol Neurobiol (2020). 2020. ↩︎
Kaufmann et al. Increased 5-lipoxygenase expression in ALS spinal cord, Ann Neurol (2018). 2018. ↩︎
Brophy et al. 15-HETE promotes dopaminergic neuron survival, Proc Natl Acad Sci (2022). 2022. ↩︎