Genetic Links Between Melatonin and Neurological Diseases

Emerging evidence demonstrates the potential neuroprotective function of melatonin against neurodegenerative diseases. In a recent genome-wide association study for melatonin secretion, we identified five genetic loci associated with melatonin secretion, including ZFHX3, GALNT13, GALNT15, LDLRAD3, and SEPP1. Here we review the biological function of these genes in respective of neuroprotection. The ZFHX3 gene encodes a transcription factor highly expressed in the suprachiasmatic nucleus. Mutation of Zfhx3 in mice modulates circadian rhythm through direct interaction with the AT motifs of downstream circadian genes. ZFHX3 also activates ATM, a kinase that activates multiple downstream proteins important for DNA repair. The activation of ATM in cytoplasm protects cerebellar neurons from genotoxic damage. GALNT13 and GALNT15 are implicated in mucin-type O-glycosylation, but whether they have a role in neurodegenerative diseases is to be elucidated. The LDLRAD3 gene belongs to the low-density lipoprotein receptor gene family. LDLRAD3 associates with C99, the β-secretase product of amyloid precursor protein, which may shift the non-amyloidogenic α-secretase pathway to the amyloidogenic β-secretase pathway. In addition, C99 accumulation in neurons contributes to neuronal death. C99 is degraded through the endosomal-lysosomal pathway and the association of LDLRAD3 with C99 may modulate the degradation of C99 and accumulation in neurons. The SEPP1 gene encodes the selenoprotein P, a transporter of selenium for maintaining the selenium pool, which is subsequently taken up by neurons via the apolipoprotein E receptor 2. Selenium is the essential component of many anti-oxidative proteins, such as glutathione peroxidases and thioredoxins. Mutation of Sepp1 causes extensive brain damage, including poor motor coordination, impaired spatial learning, cognitive decline, and increased tau phosphorylation. These data provide a genetic link between melatonin and neurodegenerative diseases.