A novel approach to investigate a rare Frontotemporal Disorder: proteomic studies about Nasu-Hakola Disease

Frontotemporal dementias (FTD) include a large spectrum of pathologies based on different triggers. Among the FTD related to genetic causes and behavioral disorders (bvFTD), a rare recessively inherited systemic disorder named Nasu-Hakola Disease (NHD) is worthy of note. It is phenotypically characterized by simultaneous impairment of nervous and skeletal systems and genetically related to a structural defect of the two genes DAP12 and TREM2. These genes encode for different subunits of the membrane receptor signaling complex and are expressed by cells of both systems involved. To date, the diagnosis of NHD is carried out by genetic or psychological tests only; no biochemical/molecular studies being available to obtain an early diagnosis or a follow-up of the NHD progression. In the present study we used MudPIT (Multidimensional Protein Identification Technology) approach for the characterization of Lymphoblastoid cells from NHD patients and healthy controls. Aim of this research was to obtain a more complete picture about the mechanisms involved into NHD onset and to evaluate the presence of possible blood biomarkers of this pathology. Specifically, two NHD patients (DS), four healthy carriers (HC) and one healthy subject (HS) belonging to the same Italian family have been submitted to blood withdrawal to isolate and immortalize the B-Lymphocytes. MudPIT allowed the identification of more than 3000 distinct proteins, a number 100-fold higher than that of proteins identified by gel electrophoresis (2-DE) [Giuliano et al. PLoS One 2014; 9]. The comparison of protein profiles from DS, HC and HS groups by means of MAProMa software showed that 10% of identified proteins was peculiar of each group. In addition, network analysis of proteomics data evidenced the disease-related pathways, such as energy metabolism, including glucose pathway. This work represents a proof of principle for characterizing dysregulated proteins and related metabolic pathways involved in functional alterations of this pathology.