TY - JOUR T1 - Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3. JF - Stem Cell Reports Y1 - 2021 A1 - Chandrasekaran, Abinaya A1 - Dittlau, Katarina Stoklund A1 - Corsi, Giulia I A1 - Haukedal, Henriette A1 - Doncheva, Nadezhda T A1 - Ramakrishna, Sarayu A1 - Ambardar, Sheetal A1 - Salcedo, Claudia A1 - Schmidt, Sissel I A1 - Zhang, Yu A1 - Cirera, Susanna A1 - Pihl, Maria A1 - Schmid, Benjamin A1 - Nielsen, Troels Tolstrup A1 - Nielsen, Jørgen E A1 - Kolko, Miriam A1 - Kobolák, Julianna A1 - Dinnyés, András A1 - Hyttel, Poul A1 - Palakodeti, Dasaradhi A1 - Gorodkin, Jan A1 - Muddashetty, Ravi S A1 - Meyer, Morten A1 - Aldana, Blanca I A1 - Freude, Kristine K AB -

Frontotemporal dementia type 3 (FTD3), caused by a point mutation in the charged multivesicular body protein 2B (CHMP2B), affects mitochondrial ultrastructure and the endolysosomal pathway in neurons. To dissect the astrocyte-specific impact of mutant CHMP2B expression, we generated astrocytes from human induced pluripotent stem cells (hiPSCs) and confirmed our findings in CHMP2B mutant mice. Our data provide mechanistic insights into how defective autophagy causes perturbed mitochondrial dynamics with impaired glycolysis, increased reactive oxygen species, and elongated mitochondrial morphology, indicating increased mitochondrial fusion in FTD3 astrocytes. This shift in astrocyte homeostasis triggers a reactive astrocyte phenotype and increased release of toxic cytokines, which accumulate in nuclear factor kappa b (NF-κB) pathway activation with increased production of CHF, LCN2, and C3 causing neurodegeneration.

VL - 16 IS - 11 ER - TY - JOUR T1 - Lithium response in bipolar disorder correlates with improved cell viability of patient derived cell lines. JF - Sci Rep Y1 - 2020 A1 - Paul, Pradip A1 - Iyer, Shruti A1 - Nadella, Ravi Kumar A1 - Nayak, Rashmitha A1 - Chellappa, Anirudh S A1 - Ambardar, Sheetal A1 - Sud, Reeteka A1 - Sukumaran, Salil K A1 - Purushottam, Meera A1 - Jain, Sanjeev A1 - Viswanath, Biju AB -

Lithium is an effective, well-established treatment for bipolar disorder (BD). However, the mechanisms of its action, and reasons for variations in clinical response, are unclear. We used neural precursor cells (NPCs) and lymphoblastoid cell lines (LCLs), from BD patients characterized for clinical response to lithium (using the "Alda scale" and "NIMH Retrospective Life chart method"), to interrogate cellular phenotypes related to both disease and clinical lithium response. NPCs from two biologically related BD patients who differed in their clinical response to lithium were compared with healthy controls. RNA-Seq and analysis, mitochondrial membrane potential (MMP), cell viability, and cell proliferation parameters were assessed, with and without in vitro lithium. These parameters were also examined in LCLs from 25 BD patients (16 lithium responders and 9 non-responders), and 12 controls. MMP was lower in both NPCs and LCLs from BD; but it was reversed with in vitro lithium only in LCLs, and this was unrelated to clinical lithium response. The higher cell proliferation observed in BD was unaffected by in vitro lithium. Cell death was greater in BD. However, LCLs from clinical lithium responders could be rescued by addition of in vitro lithium. In vitro lithium also enhanced BCL2 and GSK3B expression in these cells. Our findings indicate cellular phenotypes related to the disease (MMP, cell proliferation) in both NPCs and LCLs; and those related to clinical lithium response (cell viability, BCL2/GSK3B expression) in LCLs.

VL - 10 IS - 1 ER -