Frontotemporal Dementia Patient Neurons With Progranulin Deficiency Display Protein Dyshomeostasis.

Haploinsufficiency of progranulin (PGRN) causes frontotemporal dementia (FTD), a devastating neurodegenerative disease with no effective treatment. PGRN is required for efficient proteostasis, as loss of neuronal PGRN results in dysfunctional lysosomes and impaired clearance and cytoplasmic aggregation of TDP-43, a protein involved in neurodegeneration in FTD. These and other events lead to neurodegeneration and neuroinflammation. However, the detailed mechanisms leading to protein dyshomeostasis in PGRN-deficient cells remain unclear. We report here the development of human cell models of FTD with PGRN-deficiency to explore the molecular mechanisms underlying proteostasis breakdown and TDP-43 aggregation in FTD. Neurons differentiated from FTD patient induced pluripotent stem cells (iPSCs) have reduced PGRN levels, and the neurons recapitulate key disease features, including impaired lysosomal function, defective TDP-43 turnover and accumulation, neurodegeneration, and death. Proteomic analysis revealed altered levels of proteins linked to the autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS) in FTD patient neurons, providing new mechanistic insights into the link between PGRN-deficiency and disease pathobiology.

Factors influencing the outcome of regenerative therapy in mandibular Class II furcations: Part I.

BACKGROUND: Factors influencing the outcome of regenerative therapy of Class II furcations are incompletely and poorly understood. The purpose of this 24-month prospective study was to examine the relationship of patient-, site-, and treatment-related factors to the clinical closure of randomly selected mandibular Class II furcations. Results of therapy were evaluated at 1 and 2 years postoperatively. One-year outcome data are presented in this report. METHODS: A total of 43 otherwise healthy individuals with chronic periodontitis (26 male, 17 female), 36 to 70 years of age, completed the 12-month evaluation of the study. Entry criteria included clinical and radiographic evidence of two or more mandibular facial Class II furcation defects (> or = 3 mm horizontal probing depth). Surgical therapy was completed by four periodontists (two each) in either a university clinic or private practice. Each patient contributed two furcation defects that were treated by combination therapy using an expanded polytetrafluoroethylene (ePTFE) membrane and demineralized freeze-dried bone allograft (DFDBA). Clinical measurements included a gingival index, plaque index, mobility, and, referencing an occlusal stent, probing depth (PD), probing attachment level-vertical (PAL-V), and probing attachment level-horizontal (PAL-H). Multiple linear measurements were recorded for each site clinically and after surgical debridement to characterize defect morphology, root configuration, and barrier placement. Defect volume was computed mathematically. Postsurgical maintenance care was provided at 1 to 2, 4, 6, and 8 weeks, and then biweekly until 3 months, with subsequent supportive periodontal maintenance visits at 3-month intervals. The clinical status of the furcation (open or closed), measured by a non-treating periodontist at 1 and 2 years, was the primary outcome measure. The association of patient-related factors (e.g., smoking), site-related factors (e.g., root configuration and defect morphology), and treatment-related factors (e.g., membrane exposure) to clinical status of furcations was assessed using random effects hierarchical logistic regression analysis, controlling for design and demographic variables. Non-parametric analysis was used for specific group comparisons. RESULTS: Complete clinical closure was achieved in 74% of all sites. Of the residual furcation defects, 68% were reduced to Class I. No defects progressed to Class III. Significant improvements in mean PD and PAL-V were obtained following surgical therapy. Although the proportion of sites demonstrating complete furcation closure was comparable for smokers and non-smokers, the proportion of Class II residual defects was significantly higher among smokers than non-smokers (62.5% versus 14.3%, respectively). Increases in presurgical PAL-H were associated with monotonic decreases in the percentage of sites demonstrating complete clinical closure, with only 53% of lesions > or = 5 mm responding with complete closure. Similarly, significant reductions in the frequency of clinical closure were associated with increases in the distance between the roof of furcation and crest of bone, roof of furcation and base of defect, depth of horizontal defect, and divergence of roots at the crest of bone. CONCLUSIONS: The successful clinical closure of Class II furcations was achievable at 1 year following combination therapy with an ePTFE membrane and DFDBA. The highest frequency of clinical furcation closure was observed in early Class II defects. Furcations with vertical or horizontal bone loss of 5 mm or greater responded with the lowest frequency of complete clinical closure. Nevertheless, complete furcation closure was achievable in 50% of molars with extensive bone loss. Also, 15 out of 22 (68%) of all residual defects were reduced to Class I and only seven (8%) failed to improve, demonstrating that successful clinical resolution of advanced defects remains an attainable goal.