Abstract
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 (UCP4/SLC25A27) gene affects the risk of late onset Alzheimer's disease (LOAD), and that the variant's effect is strongly dependent on APOE-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 APOE-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 APOE-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 UCP4. If validated, the involvement of UCP4 in both FTD and LOAD might indicate interesting shared etiological factors which might give future therapeutic clues.
Highlights
Neurodegenerative diseases comprise one of the major public health concerns worldwide, with Alzheimer’s disease (AD), Frontotemporal disease (FTD), and Parkinson’s disease (PD) being the most common types
We recently reported that rs9472817‐C/G, an intronic variant of neuronal mitochondrial uncoupling protein‐4 (UCP4/SLC25A27) gene affects the risk of late onset Alzheimer's disease (LOAD), and that the variant's effect is strongly dependent on APOE‐ε4 status
In sporadic frontotemporal dementia (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 APOE‐ε4
Summary
Neurodegenerative diseases comprise one of the major public health concerns worldwide, with Alzheimer’s disease (AD), Frontotemporal disease (FTD), and Parkinson’s disease (PD) being the most common types These diseases are considered distinct entities, each with its distinct etiological mechanisms, affected brain regions and clinical characteristics, they share some common features. Evidences suggest that genetic variants within the HLA locus contribute to the www.aging‐us.com development of these disorders [8,9,10]. Taken together, such overlapping features may reflect some common underlying etiological factors
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