Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer’s disease
(2025) Alzheimer’s Research and Therapy, 17 (1), art. no. 5, .
Valdes, P.a b , Caldwell, A.B.a , Liu, Q.c i , Fitzgerald, M.Q.a b , Ramachandran, S.a , Karch, C.M.e , Xu, X.k , Xu, J.k , Xiong, C.k , Weamer, E.k , Wang, Q.k , Wang, P.k , Vöglein, J.k , Thompson, S.k , Taddei, K.k , Stephens, S.k , Sohrabi, H.k , Snitz, B.k , Smith, L.k , Smith, J.k , Sigurdson, W.k , Shimada, H.k , Shady, K.k , Seyfried, N.T.k , Senda, M.k , Schofield, P.k , Salloway, S.k , Ringman, J.k , Renton, A.k , Preische, O.k , Ping, L.k , Perrin, R.k , Patira, R.k , O’Connor, A.k , Obermüller, U.k , Nuscher, B.k , Norton, J.k , Noble, J.k , Niimi, Y.k , Neimeyer, K.k , Nagamatsu, A.k , Nadkarni, N.k , Mummery, C.k , Mountz, J.k , Morris, J.k , Morenas-Rodriguez, E.k , Mejia, A.k , McDade, E.k , McCullough, A.k , Mawuenyega, K.k , Masters, C.k , Mason, N.S.k , Martins, R.k , Marsh, J.k , Lopez, O.k , Li, Y.k , Levin, J.k , Levey, A.k , Laske, C.k , Kuder-Buletta, E.k , Koudelis, D.k , Koeppe, R.k , Klunk, W.k , Keefe, S.k , Kasuga, K.k , Käser, S.k , Jucker, M.k , Johnson, E.k , Jerome, G.k , Jack, C.k , Ishii, K.k , Ikonomovic, S.k , Ikeuchi, T.k , Ihara, R.k , Igor, Y.k , Hornbeck, R.k , Holtzman, D.k , Hofmann, A.k , Hoechst-Swisher, L.k , Herries, E.k , Hellm, C.k , Hassenstab, J.k , Häsler, L.k , Haass, C.k , Groves, A.k , Grilo, M.k , Gremminger, E.k , Gray, J.k , Graham, M.k , Graff-Radford, N.k , Gräber-Sultan, S.k , Gordon, B.k , Gonzalez, A.k , Goldman, J.k , Goldberg, S.k , Goate, A.k , Ghetti, B.k , Gardener, S.k , Fujii, H.k , Joseph-Mathurin, N.k , Franklin, E.k , Fox, N.k , Flores, S.k , Fitzpatrick, C.k , Feldman, B.k , Farlow, M.k , Fagan, A.k , Esposito, B.k , Egido, N.k , Duong, D.k , Douglas, J.k , Donahue, T.k , Dincer, A.k , Diffenbacher, A.k , Denner, D.k , DeLaCruz, C.k , Day, G.S.k , Cruchaga, C.k , Courtney, L.k , Chui, H.k , Chua, J.k , Mendez, P.C.k , Chhatwal, J.k , Chen, C.k , Cash, L.k , Carter, K.k , Buckles, V.k , Buck, J.k , Brosch, J.k , Brooks, W.B.k , Brandon, S.k , Bodge, C.k , Berman, S.k , Benzinger, T.k , Bechara, J.k , Bateman, R.k , Barthelemy, N.k , Araki, A.k , Allegri, R.k , Adams, S.k , Galasko, D.R.c , Yuan, S.H.c j , Wagner, S.L.c d , Subramaniam, S.a f g h , Dominantly Inherited Alzheimer Network (DIAN)k
a Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, United States
b Bioengineering Graduate Program, University of California, San Diego, La Jolla, CA 92093, United States
c Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, United States
d VA San Diego Healthcare System, San Diego, CA 92161, United States
e Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
f Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, United States
g Department of Nanoengineering, University of California, San Diego, La Jolla, CA 92093, United States
h Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093, United States
i Present Address: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego, La Jolla, CA 92093, United States
j Present Address: N. Bud Grossman Center for Memory Research and Care, Department of Neurology, University of Minnesota, GRECC, Minneapolis VA Health Care System, Minneapolis, MN 55417, United States
Abstract
Background: PSEN1, PSEN2, and APP mutations cause Alzheimer’s disease (AD) with an early age at onset (AAO) and progressive cognitive decline. PSEN1 mutations are more common and generally have an earlier AAO; however, certain PSEN1 mutations cause a later AAO, similar to those observed in PSEN2 and APP. Methods: We examined whether common disease endotypes exist across these mutations with a later AAO (~ 55 years) using hiPSC-derived neurons from familial Alzheimer’s disease (FAD) patients harboring mutations in PSEN1A79V, PSEN2N141I, and APPV717I and mechanistically characterized by integrating RNA-seq and ATAC-seq. Results: We identified common disease endotypes, such as dedifferentiation, dysregulation of synaptic signaling, repression of mitochondrial function and metabolism, and inflammation. We ascertained the master transcriptional regulators associated with these endotypes, including REST, ASCL1, and ZIC family members (activation), and NRF1 (repression). Conclusions: FAD mutations share common regulatory changes within endotypes with varying severity, resulting in reversion to a less-differentiated state. The regulatory mechanisms described offer potential targets for therapeutic interventions. © The Author(s) 2025.
Document Type: Article
Publication Stage: Final
Source: Scopus
Precocious Puberty in Children with Neurofibromatosis Type 1
(2025) Journal of Pediatrics, 278, art. no. 114440, .
Katz, J.a , Ratnam, S.b , Listernick, R.H.c , Habiby, R.L.b , Gutmann, D.H.d
a Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
b Division of Endocrinology, Ann & Robert H. Lurie Children’s Hospital, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
c Division of Academic General Pediatrics and Primary Care, Ann & Robert H. Lurie Children’s Hospital, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
This multi-institutional, descriptive study of 19 children with neurofibromatosis 1 examines the link between optic pathway gliomas (OPGs) and central precocious puberty (CPP). We report that CPP can arise without OPG chiasmal involvement and that prior OPG chemotherapy does not prevent the development of CPP. © 2024 Elsevier Inc.
Author Keywords
neurofibromatosis; NF1; optic pathway glioma; precocious puberty
Document Type: Article
Publication Stage: Final
Source: Scopus
Fate erasure logic of gene networks underlying direct neuronal conversion of somatic cells by microRNAs
(2025) Cell Reports, 44 (1), art. no. 115153, .
Cates, K.a c d , Yuan, L.a c , Yang, Y.a , Yoo, A.S.a b
a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
c Program in Molecular Genetics and Genomics, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Genetics, Stanford University, Stanford, CA 94305, United States
Abstract
Neurogenic microRNAs 9/9∗ and 124 (miR-9/9∗-124) drive the direct reprogramming of human fibroblasts into neurons with the initiation of the fate erasure of fibroblasts. However, whether the miR-9/9∗-124 fate erasure logic extends to the neuronal conversion of other somatic cell types remains unknown. Here, we uncover that miR-9/9∗-124 induces neuronal conversion of multiple cell types: dura fibroblasts, astrocytes, smooth muscle cells, and pericytes. We reveal the cell-type-specific and pan-somatic gene network erasure induced by miR-9/9∗-124, including cell cycle, morphology, and proteostasis gene networks. Leveraging these pan-somatic gene networks, we predict upstream regulators that may antagonize somatic fate erasure. Among the predicted regulators, we identify TP53 (p53), whose inhibition is sufficient to enhance neuronal conversion even in post-mitotic cells. This study extends miR-9/9∗-124 reprogramming to alternate somatic cells, reveals the pan-somatic gene network fate erasure logic of miR-9/9∗-124, and shows a neurogenic role for p53 inhibition in the miR-9/9∗-124 signaling cascade. © 2024 The Author(s)
Author Keywords
cell fate; CP: Molecular biology; CP: Stem cell research; direct conversion; fate erasure; microRNA; neuronal reprogramming; transcriptomics
Document Type: Article
Publication Stage: Final
Source: Scopus