Uncoupling Protein 4 () Gene Variability in Neurodegenerative Disorders: Further Evidence of Association in Frontotemporal Dementia

Ongoing research suggests that mitochondrial dysfunction is a common hallmark in neurodegenerative diseases, pointing to mitochondrial uncoupling process as a critical player. We recently reported that rs9472817-C/G, an intronic variant of neuronal mitochondrial uncoupling protein-4 () gene affects the risk of late onset Alzheimer's disease (LOAD), and that the variant's effect is strongly dependent on -ε4 status. Here, we extended our analysis to a cohort of 751 subjects including late-onset familial and sporadic cases of frontotemporal dementia (FTD; 213), Parkinson disease (PD;96), and 442 healthy controls. In all subgroups, carriers of -ε4 allele were at higher risk of disease. Regarding the rs9472817, no association was detected in familial FTD and both subgroups of PD patients. In sporadic FTD, as in LOAD, we found that the C allele increased the risk of disease of about 1.51-fold in a dose-dependent manner (p=0.013) independently from that conferred by -ε4. Expression quantitative trait loci (eQTL) data of different brain regions suggest that rs9472817 likely exerts its effect by a cis-regulatory mechanism involving modulation of . If validated, the involvement of UCP4 in both FTD and LOAD might indicate interesting shared etiological factors which might give future therapeutic clues.