A novel network analysis approach reveals DNA damage, oxidative stress and calcium/cAMP homeostasis-associated biomarkers in frontotemporal dementia

Abstract

Frontotemporal Dementia (FTD) is the form of neurodegenerative dementia with the highest prevalence after Alzheimer’s disease, equally distributed in men and women. It includes several variants, generally characterized by behavioural instability and language impairments. Although few mendelian genes (MAPT, GRN, and C9orf72) have been associated to the FTD phenotype, in most cases there is only evidence of multiple risk loci with relatively small effect size. To date, there are no comprehensive studies describing FTD at molecular level, highlighting possible genetic interactions and signalling pathways at the origin FTD-associated neurodegeneration. In this study, we designed a broad FTD genetic interaction map of the Italian population, through a novel network-based approach modelled on the concepts of disease-relevance and interaction perturbation, combining Steiner tree search and Structural Equation Model (SEM) analysis. Our results show a strong connection between Calcium/cAMP metabolism, oxidative stress-induced Serine/Threonine kinases activation, and postsynaptic membrane potentiation, suggesting a possible combination of neuronal damage and loss of neuroprotection, leading to cell death. In our model, Calcium/cAMP homeostasis and energetic metabolism impairments are primary causes of loss of neuroprotection and neural cell damage, respectively. Secondly, the altered postsynaptic membrane potentiation, due to the activation of stress-induced Serine/Threonine kinases, leads to neurodegeneration. Our study investigates the molecular underpinnings of these processes, evidencing key genes and gene interactions that may account for a significant fraction of unexplained FTD aetiology. We emphasized the key molecular actors in these processes, proposing them as novel FTD biomarkers that could be crucial for further epidemiological and molecular studies.

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

“…While dysregulation of calcium is well documented in AD, studies addressing this pathway in FTD are scarce. A network-based approach suggested that impairment in calcium/cAMP and energetic metabolism are the primary causative factors in the neuronal cell death in FTD [53]. The impairment of these pathways was observed particularly in astrocytes, suggesting that the loss of calcium/cAMP homeostasis may be involved in the progressive neurodegeneration in FTD.…”

Altered serum protein levels in frontotemporal dementia and amyotrophic lateral sclerosis indicate calcium and immunity dysregulation

“…The drug Riluzole currently used to treat ALS works via inhibiting calcium signaling 37 . In a functional network study of an independent cohort of sporadic FTD patients, calcium/cAMP homeostasis and energetic metabolism impairments were identified as primary causes of the loss of neuroprotection and neural cell damage in FTD 36 . The authors suggested that calcium homeostasis in addition to DNA damage and oxidative stress could be among major molecular underpinnings for a significant proportion of unexplained FTD etiology 36 .…”

“…In a functional network study of an independent cohort of sporadic FTD patients, calcium/cAMP homeostasis and energetic metabolism impairments were identified as primary causes of the loss of neuroprotection and neural cell damage in FTD 36 . The authors suggested that calcium homeostasis in addition to DNA damage and oxidative stress could be among major molecular underpinnings for a significant proportion of unexplained FTD etiology 36 . In separate studies, calcium dysregulation was reported to contribute to neurodegeneration in iPSC-derived neurons from FTD patients 38 and ALS patients 39 .…”

Uncovering pathophysiological changes in frontotemporal dementia using serum lipids

“…Furthermore, we analyzed calcium levels as a measure of LPC levels; increases in LPC www.nature.com/scientificreports www.nature.com/scientificreports/ levels induce increases in calcium levels via G-protein-coupled receptors 40 . Calcium dysregulation is also associated with FTD 41,42 . We found that calcium levels were significantly increased in FTD serum compared to controls (Fig.…”