Synapsin Condensation is Governed by Sequence-Encoded Molecular Grammars
(2025) Journal of Molecular Biology, 437 (8), art. no. 168987, .
Hoffmann, C.a , Ruff, K.M.b , Edu, I.A.c , Shinn, M.K.b , Tromm, J.V.a , King, M.R.b , Pant, A.b , Ausserwöger, H.c , Morgan, J.R.d , Knowles, T.P.J.c e , Pappu, R.V.b , Milovanovic, D.a f g h
a Laboratory of Molecular Neuroscience Berlin, German Center for Neurodegenerative Diseases (DZNE), Berlin, 10117, Germany
b Department of Biomedical Engineering and Center for Biomolecular Condensates, James McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, United States
c Centre for Misfolding Diseases, Yusuf Hamied, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom
d Eugene Bell Center for Regenerative Biology and Tissue Engineering, Marine Biological Laboratory, Woods HoleMA 02543, United States
e Cavendish Laboratory, Department of Physics, University of Cambridge, JJ Thomson Road, Cambridge, CB3 0HE, United Kingdom
f German Center for Neurodegenerative Diseases (DZNE), Bonn, 53127, Germany
g Einstein Center for Neuroscience, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Berlin, 10117, Germany
h Whitman Center, Marine Biological Laboratory, 02543 Woods HoleMA, United States
Abstract
Multiple biomolecular condensates coexist at the pre- and post- synapse to enable vesicle dynamics and controlled neurotransmitter release in the brain. In pre-synapses, intrinsically disordered regions (IDRs) of synaptic proteins are drivers of condensation that enable clustering of synaptic vesicles (SVs). Using computational analysis, we show that the IDRs of SV proteins feature evolutionarily conserved non-random compositional biases and sequence patterns. Synapsin-1 is essential for condensation of SVs, and its C-terminal IDR has been shown to be a key driver of condensation. Focusing on this IDR, we dissected the contributions of two conserved features namely the segregation of polar and proline residues along the linear sequence, and the compositional preference for arginine over lysine. Scrambling the blocks of polar and proline residues weakens the driving forces for forming micron-scale condensates. However, the extent of clustering in subsaturated solutions remains equivalent to that of the wild-type synapsin-1. In contrast, substituting arginine with lysine significantly weakens both the driving forces for condensation and the extent of clustering in subsaturated solutions. Co-expression of the scrambled variant of synapsin-1 with synaptophysin results in a gain-of-function phenotype in cells, whereas arginine to lysine substitutions eliminate condensation in cells. We report an emergent consequence of synapsin-1 condensation, which is the generation of interphase pH gradients that is realized via differential partitioning of protons between coexisting phases. This pH gradient is likely to be directly relevant for vesicular ATPase functions and the loading of neurotransmitters. Our studies highlight how conserved IDR grammars serve as drivers of synapsin-1 condensation. © 2025 The Author(s)
Author Keywords
interphase pH gradient; microfluidics; phase separation; synapse; synapsin 1
Funding details
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
National Institutes of HealthNIH
European Research CouncilERC101078172, 101001615
European Research CouncilERC
Air Force Office of Scientific ResearchAFOSRFA9550-20-1-0241
Air Force Office of Scientific ResearchAFOSR
National Institute on AgingNIA2RF1 NS078165-12
National Institute on AgingNIA
Deutsche ForschungsgemeinschaftDFGSFB1286/B10, MI 2104
Deutsche ForschungsgemeinschaftDFG
National Science FoundationNSFMCB-2227268
National Science FoundationNSF
National Institute of Neurological Disorders and StrokeNINDSF32GM146418-01A1, R01NS121114, K99GM152778
National Institute of Neurological Disorders and StrokeNINDS
Document Type: Article
Publication Stage: Final
Source: Scopus
Loss of ATG7 in microglia impairs UPR, triggers ferroptosis, and weakens amyloid pathology control
(2025) The Journal of Experimental Medicine, 222 (4), .
Cai, Z.a , Wang, S.a b , Cao, S.a , Chen, Y.a , Penati, S.a , Peng, V.a c , Yuede, C.M.d , Beatty, W.L.e , Lin, K.a , Zhu, Y.a , Zhou, Y.a f , Colonna, M.a
a Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
b School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
c Department of Medicine, University of California San Francisco, San Francisco, CA, United States
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
e Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, United States
Abstract
Microglia impact brain development, homeostasis, and pathology. One important microglial function in Alzheimer’s disease (AD) is to contain proteotoxic amyloid-β (Aβ) plaques. Recent studies reported the involvement of autophagy-related (ATG) proteins in this process. Here, we found that microglia-specific deletion of Atg7 in an AD mouse model impaired microglia coverage of Aβ plaques, increasing plaque diffusion and neurotoxicity. Single-cell RNA sequencing, biochemical, and immunofluorescence analyses revealed that Atg7 deficiency reduces unfolded protein response (UPR) while increasing oxidative stress. Cellular assays demonstrated that these changes lead to lipoperoxidation and ferroptosis of microglia. In aged mice without Aβ buildup, UPR reduction and increased oxidative damage induced by Atg7 deletion did not impact microglia numbers. We conclude that reduced UPR and increased oxidative stress in Atg7-deficient microglia lead to ferroptosis when exposed to proteotoxic stress from Aβ plaques. However, these microglia can still manage misfolded protein accumulation and oxidative stress as they age. © 2025 Cai et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep
(2025) Proceedings of the National Academy of Sciences of the United States of America, 122 (8), pp. e2416578122.
Constantino, N.J.a b c , Carroll, C.M.d , Williams, H.C.a c , Vekaria, H.J.b e , Yuede, C.M.f g , Saito, K.b c , Sheehan, P.W.g , Snipes, J.A.a c , Raichle, M.E.g h i j k , Musiek, E.S.g , Sullivan, P.G.b e , Morganti, J.M.b c , Johnson, L.A.a c , Macauley, S.L.a b c
a Department of Physiology, University of Kentucky, Lexington, United States
b Department of Neuroscience, University of Kentucky, Lexington, United States
c Sanders Brown Center on Aging, University of Kentucky, Lexington, United States
d Department of Psychiatry, Wake Forest School of Medicine, Winston-Salem
e Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
g Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
h Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
i Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
j Department of Psychology & Brain Sciences, Washington University, St. Louis, MO 63110, United States
k Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Metabolism plays a key role in the maintenance of sleep/wake states. Brain lactate fluctuations are a biomarker of sleep/wake transitions, where increased interstitial fluid (ISF) lactate levels are associated with wakefulness and decreased ISF lactate is required for sleep. ATP-sensitive potassium (KATP) channels couple glucose-lactate metabolism with excitability. Using mice lacking KATP channel activity (e.g., Kir6.2-/- mice), we explored how changes in glucose utilization affect cortical electroencephalography (EEG) activity and sleep/wake homeostasis. In the brain, Kir6.2-/- mice shunt glucose toward glycolysis, reducing neurotransmitter biosynthesis and dampening cortical EEG activity. Kir6.2-/- mice spent more time awake at the onset of the light period due to altered ISF lactate dynamics. Together, we show that Kir6.2-KATP channels act as metabolic sensors to gate arousal by maintaining the metabolic stability of sleep/wake states and providing the metabolic flexibility to transition between states.
Author Keywords
arousal; excitability; KATP channels; metabolism; sleep
Document Type: Article
Publication Stage: Final
Source: Scopus
Chromosomal and gonadal sex have differing effects on social motivation in mice
(2025) Biology of Sex Differences, 16 (1), p. 13.
Chaturvedi, S.M.a b , Sarafinovska, S.a b , Selmanovic, D.a b , McCullough, K.B.a b , Swift, R.G.a b , Maloney, S.E.b c , Dougherty, J.D.a b c
a Department of Genetics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
c Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63130, United States
Abstract
BACKGROUND: Sex differences in brain development are thought to lead to sex variation in social behavior. Sex differences are fundamentally driven by both gonadal hormones and sex chromosomes, yet little is known about the independent effects of each on social behavior. Further, mouse models of the genetic liability for the neurodevelopmental disorder MYT1L Syndrome have shown sex-specific deficits in social motivation. In this study, we aimed to determine if gonadal hormones or sex chromosomes primarily mediate the sex differences seen in mouse social behavior, both at baseline and in the context of Myt1l haploinsufficiency. METHODS: Four-core genotypes (FCG) mice, which uncouple gonadal and chromosomal sex, were crossed with MYT1L heterozygous mice to create eight different groups with unique combinations of sex factors and MYT1L genotype. A total of 131 mice from all eight groups were assayed for activity and social behavior via the open field and social operant paradigms. Measures of social seeking and orienting were analyzed for main effects of chromosome, gonads, and their interactions with Myt1l mutation. RESULTS: The FCGxMYT1L cross revealed independent effects of both gonadal and chromosomal sex on activity and social behavior. Specifically, the presence of ovarian hormones led to greater overall activity, social seeking, and social orienting regardless of MYT1L genotype. In contrast, sex chromosomes affected social behavior mainly in the MYT1L heterozygous group, with XX MYT1L mutant mice demonstrating elevated levels of social orienting and seeking compared to XY MYT1L mutant mice. CONCLUSIONS: Gonadal and chromosomal sex have independent mechanisms of driving greater social motivation in females. Additionally, genes on the sex chromosomes may interact with neurodevelopmental risk genes to influence sex variation in atypical social behavior. © 2025. The Author(s).
As our brain develops, many factors influence how we behave later in life. The brain forms differently in males and females, potentially leading to sex variation seen in many behaviors including sociability. In addition, conditions defined by differences in social behaviors, such as autism, are diagnosed more in males than females. However, researchers don’t know exactly how distinct sex factors, such as gonadal hormones and sex chromosome genes, lead to different behaviors in males and females. In this study, we used mouse models and tests of mouse behavior to explore these differences. Results show that gonadal hormones primarily contributed to differences in social motivation between sexes. Yet, when we repeated these same assays in a mouse model of genetic liability for a human neurodevelopmental syndrome, we found that sex chromosome genes rather than gonadal hormones played a larger role in the behavioral consequences of impaired neurodevelopment. These insights can inform future research on the biological mechanisms of social behavior in the context of genetic liability for neurodevelopmental disorders.
Author Keywords
Gonadal hormones; Mouse models; MYT1L syndrome; Neurodevelopmental disorders; Sex chromosomes; Sex differences; Social behavior
Document Type: Article
Publication Stage: Final
Source: Scopus
Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial
(2025) JAMA Network Open, 8 (2), p. e2459058.
Paganoni, S.a b , Fournier, C.N.c , Macklin, E.A.a d , Chibnik, L.B.a d e , Quintana, M.f , Saville, B.R.f , Detry, M.A.f , Vestrucci, M.f , Marion, J.f , McGlothlin, A.f , Ajroud-Driss, S.g , Chase, M.a , Pothier, L.a , Harkey, B.A.a , Yu, H.a , Sherman, A.V.a , Shefner, J.M.h , Hall, M.h , Kittle, G.h , Berry, J.D.a , Babu, S.a , Andrews, J.i , Dagostino, D.a , Tustison, E.a , Giacomelli, E.a , Scirocco, E.a , Alameda, G.j , Locatelli, E.j k , Ho, D.a , Quick, A.l , Katz, J.m , Heitzman, D.n , Appel, S.H.o , Shroff, S.o , Felice, K.p , Maragakis, N.J.q , Simmons, Z.r , Miller, T.M.s , Olney, N.t , Weiss, M.D.u , Goutman, S.A.v , Fernandes, J.A.w , Jawdat, O.x , Owegi, M.A.y , Foster, L.A.z , Vu, T.aa , Ilieva, H.ab , Newman, D.S.ac , Arcila-Londono, X.ac , Jackson, C.E.ad , Ladha, S.h , Heiman-Patterson, T.ae , Caress, J.B.af , Swenson, A.ag , Peltier, A.ah , Lewis, R.ai , Fee, D.aj , Elliott, M.ak , Bedlack, R.al , Kasarskis, E.J.am , Elman, L.an , Rosenfeld, J.ao , Walk, D.ap , McIlduff, C.aq , Twydell, P.ar , Young, E.as , Johnson, K.at , Rezania, K.au , Goyal, N.A.av , Cohen, J.A.aw , Benatar, M.ax , Jones, V.ay , Glass, J.c , Shah, J.az , Beydoun, S.R.ba , Wymer, J.P.bb , Zilliox, L.bc , Nayar, S.bd , Pattee, G.L.be , Martinez-Thompson, J.bf , Harvey, B.bg , Patel, S.bg , Mahoney, P.bh , Duda, P.W.bg , Cudkowicz, M.E.a , HEALEY ALS Platform Trial Study Groupbi
a Sean M. Healey & AMG Center for ALS and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, United States
b Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, United States
c Department of Neurology, Emory University, Atlanta, Georgia
d Biostatistics Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, United States
e Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, United States
f Berry Consultants LLC, Austin, TX, United States
g Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
h Barrow Neurological Institute, Phoenix, AZ, United States
i Department of Neurology, Columbia UniversityNY, United States
j Phil Smith Neuroscience Institute, Holy Cross Hospital, Silver SpringMD, Liberia
k Department of Neurology, Nova Southeastern University, Fort Lauderdale, FL, Puerto Rico
l Department of Neurology, Ohio State University, Columbus, United States
m California Pacific Medical Center and Forbes Norris MDA-ALS Research and Treatment Center, San Francisco, Mexico
n Texas Neurology, Dallas, United States
o Methodist Neurological Institute, Houston, TX, United States
p Department of Neuromuscular Medicine, Hospital for Special Care, New Britain, CT, United States
q Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, Liberia
r Department of Neurology, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States
s Department of Neurology, Hope Center for Neurological Disorders, Washington University in St Louis, St Louis, MO, United States
t Providence ALS Clinic, Portland, Oregon
u Department of Neurology, University of Washington Medical Center, Seattle, United States
v Department of Neurology, University of Michigan, Ann Arbor, United States
w Department of Neurology, University of Nebraska Medical Center, Omaha, United States
x Departmennt of Neurology, University of Kansas Medical Center, Kansas City, United States
y Department of Neurology, University of Massachusetts Medical School, Worcester, United Kingdom
z Department of Neurology, University of Colorado School of Medicine, Aurora, United States
aa Department of Neurology, University of South Florida, Tampa, Romania
ab Jefferson Weinberg ALS Center, Philadelphia, PA, United States
ac Henry Ford Health System Department of Neurology, Detroit, MI, United States
ad Department of Neurology, University of Texas Health, San Antonio, Mexico
ae Department of Neurology, Temple Health, Philadelphia, PA, United States
af Department of Neurology, Wake Forest University School of Medicine, Winston-SalemNC, United States
ag Department of Neurology, University of Iowa, Iowa City, United States
ah Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States
ai Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
aj Department of Neurology, Medical College of Wisconsin, Milwaukee, United States
ak Department of Neurology, University of Virginia, Arlington, United Kingdom
al Department of Neurology, Duke University, Durham, NC, United States
am Department of Neurology, University of Kentucky, Lexington, United States
an Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, United States
ao Department of Neurology, Loma Linda University School of Medicine, Loma Linda, CA, United States
ap Department of Neurology, University of Minnesota/Twin Cities ALS Research Consortium, Minneapolis and St Paul
aq Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
ar Department of Neurology, Spectrum Health Medical Group, Grand RapidsMI, United States
as Department of Neurology, SUNY (State University of New York) Upstate, Syracuse, United States
at Department of Neurology, Ochsner Health System, New Orleans, LA, United States
au Department of Neurology, University of Chicago, Chicago, IL, United States
av Department of Neurology, University of California, Medical Center, Irvine, United Kingdom
aw Department of Neurology, Dartmouth-Hitchcock Medical CenterNH, Lebanon
ax Department of Neurology, University of Miami, Miami, FL, Puerto Rico
ay Department of Physical Medicine and Rehabilitation, School of Medicine, University of Missouri, Columbia, United States
az Department of Neurology, Mayo Clinic, Jacksonville, FL, Puerto Rico
ba Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, Mexico
bb Department of Neurology, University of Florida, Gainesville, United States
bc Department of Neurology, University of Maryland School of Medicine, Baltimore, United States
bd Department of Neurology, Georgetown UniversityWA, United States
be Neurology Associates, Lincoln, NE, United States
bf Department of Neurology, Mayo Clinic, Rochester, MN, United States
bg UCB Pharma, Cambridge, MA, United States
bh UCB, Slough, United Kingdom
Abstract
Importance: The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective: To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants: Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions: Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures: The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results: Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance: In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration: ClinicalTrials.gov Identifier: NCT04297683.
Document Type: Article
Publication Stage: Final
Source: Scopus
Dissociable spatial topography of cortical atrophy in early-onset and late-onset Alzheimer’s disease: A head-to-head comparison of the LEADS and ADNI cohorts
(2025) Alzheimer’s and Dementia, .
Katsumi, Y.a , Touroutoglou, A.a , Brickhouse, M.a , Eloyan, A.b , Eckbo, R.a , Zaitsev, A.a , La Joie, R.c , Lagarde, J.c , Schonhaut, D.c , Thangarajah, M.b , Taurone, A.b , Vemuri, P.d , Jack, C.R., Jr.d , Dage, J.L.e f , Nudelman, K.N.H.f , Foroud, T.f , Hammers, D.B.e , Ghetti, B.f , Murray, M.E.g , Newell, K.L.f , Polsinelli, A.J.e , Aisen, P.h , Reman, R.h , Beckett, L.i , Kramer, J.H.c , Atri, A.j , Day, G.S.k , Duara, R.l , Graff-Radford, N.R.k , Grant, I.M.m , Honig, L.S.n , Johnson, E.C.B.o , Jones, D.T.d , Masdeu, J.C.p , Mendez, M.F.q , Musiek, E.r , Onyike, C.U.s , Riddle, M.t , Rogalski, E.u , Salloway, S.b , Sha, S.v , Turner, R.S.w , Wingo, T.S.x , Wolk, D.A.y , Womack, K.r , Carrillo, M.C.z , Rabinovici, G.D.c , Apostolova, L.G.e f aa , Dickerson, B.C.a , the LEADS Consortium for the Alzheimer’s Disease Neuroimaging Initiativeab
a Frontotemporal Disorders Unit and Massachusetts Alzheimer’s Disease Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
b Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, RI, United States
c Department of Neurology, University of California – San Francisco, San Francisco, CA, United States
d Department of Radiology, Mayo Clinic, Rochester, MN, United States
e Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
f Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
g Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
h Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, United States
i Department of Public Health Sciences, University of California – Davis, Davis, CA, United States
j Banner Sun Health Research Institute, Sun City, AZ, United States
k Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
l Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami, FL, United States
m Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
n Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
o Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
p Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, TX, United States
q Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
r Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
s Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
t Department of Neurology, Alpert Medical School, Brown University, Providence, RI, United States
u Department of Neurology, University of Chicago, Chicago, IL, United States
v Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, CA, United States
w Department of Neurology, Georgetown University, Washington, DC, United States
x Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
y Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
z Medical & Scientific Relations Division, Alzheimer’s Association, Chicago, IL, United States
aa Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, IN, United States
Abstract
INTRODUCTION: Early-onset and late-onset Alzheimer’s disease (EOAD and LOAD, respectively) have distinct clinical manifestations, with prior work based on small samples suggesting unique patterns of neurodegeneration. The current study performed a head-to-head comparison of cortical atrophy in EOAD and LOAD, using two large and well-characterized cohorts (LEADS and ADNI). METHODS: We analyzed brain structural magnetic resonance imaging (MRI) data acquired from 377 sporadic EOAD patients and 317 sporadicLOAD patients who were amyloid positive and had mild cognitive impairment (MCI) or mild dementia (i.e., early-stage AD), along with cognitively unimpaired participants. RESULTS: After controlling for the level of cognitive impairment, we found a double dissociation between AD clinical phenotype and localization/magnitude of atrophy, characterized by predominant neocortical involvement in EOAD and more focal anterior medial temporal involvement in LOAD. DISCUSSION: Our findings point to the clinical utility of MRI-based biomarkers of atrophy in differentiating between EOAD and LOAD, which may be useful for diagnosis, prognostication, and treatment. Highlights: Early-onset Alzheimer’s disease (EOAD) and late-onset AD (LOAD) patients showed distinct and overlapping cortical atrophy patterns. EOAD patients showed prominent atrophy in widespread neocortical regions. LOAD patients showed prominent atrophy in the anterior medial temporal lobe. Regional atrophy was correlated with the severity of global cognitive impairment. Results were comparable when the sample was stratified for mild cognitive impairment (MCI) and dementia. © 2025 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
amnestic; atypical Alzheimer’s disease; disease signature; magnetic resonance imaging (MRI); neurodegeneration; non-amnestic
Funding details
BioClinica
National Institute of Biomedical Imaging and BioengineeringNIBIB
AbbVie
Biogen
Alzheimer’s Drug Discovery FoundationADDF
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
U.S. Department of DefenseDOD
National Institutes of HealthNIHS10RR021110, S10 RR023401, S10 RR023043
National Institutes of HealthNIH
P41 EB015896
Alzheimer’s Disease Neuroimaging InitiativeADNIU01 AG024904
Alzheimer’s Disease Neuroimaging InitiativeADNI
Alzheimer’s AssociationAAAA LDRFP‐21‐824473, AA LDRFP‐21‐828356
Alzheimer’s AssociationAA
National Institute on AgingNIAU24 AG072122
National Institute on AgingNIA
Fondation pour la Recherche sur AlzheimerU24 AG021886, R56 AG057195, U01 AG6057195
Fondation pour la Recherche sur Alzheimer
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Sleep variability and time to achieving pregnancy: findings from a pilot cohort study of women desiring pregnancy
(2025) Fertility and Sterility, .
Zhao, P.a , Jungheim, E.S.b , Bedrick, B.S.c , Wan, L.a , Jimenez, P.T.a , McCarthy, R.a , Chubiz, J.a , Fay, J.C.d , Herzog, E.D.e , Sutcliffe, S.f , England, S.K.a
a Department of Obstetrics and Gynecology, School of Medicine, Washington University, St. Louis, Missouri, United States
b Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
c Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
d Department of Biology, University of Rochester, Rochester, New York, United States
e Department of Biology, School of Arts and Sciences, Washington University in St. Louis, St. Louis, Missouri, United States
f Department of Surgery, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States
Abstract
Objective: To determine whether chronodisruption is associated with achieving pregnancy. Design: Pilot prospective cohort study. Setting: Academic Medical Center. Patient(s): One hundred eighty-three women desiring pregnancy were recruited from the local community of an academic medical center located in the Midwest and provided sleep information between February 1, 2015, and November 30, 2017. Intervention: Sleep and activity data were obtained via actigraphy watches worn continuously for 2 weeks to assess measures of chronodisruption, including sleep period onset, offset, midtime, and duration; as well as variability in each of these measures. Main Outcome Measures: Time to becoming pregnant over 1-year of follow-up. Results: Of the 183 eligible women, 82 became pregnant over a median of 2.8 months of follow-up. Greater interdaily variability in time of sleep onset and variability in sleep duration were associated with a longer time to achieving pregnancy after adjusting for age, body mass index, race, education, income, and smoking status (adjusted hazard ratio [aHR], 0.60; 95% confidence interval [CI], 0.36–0.999 comparing participants with a standard deviation of >1.8 hours to <1.8 hours in daily time of sleep onset; and aHR, 0.58; 95% CI, 0.36–0.98 comparing participants with a standard deviation of >2.3 hours to <2.3 hours in daily sleep duration). In adjusted analyses, no statistically significant associations were observed for average time of sleep onset and offset, midsleep time, and sleep duration, or for variability in time of sleep offset and midtime. Conclusions: Higher day-to-day variability in time of sleep onset and sleep duration—two measures of chronodisruption—were associated with a longer time to achieving pregnancy over 1 year of follow-up in women desiring pregnancy. If replicated in additional studies, these findings could point to lifestyle interventions to help women achieve a desired pregnancy. © 2025 The Authors
Author Keywords
chronodisruption; lifestyle modification; pregnancy success; sleep
Funding details
March of Dimes FoundationMDF
University of WashingtonUW
Department of Obstetrics and Gynecology, Baylor College of Medicine
National Institutes of HealthNIHR01 HD037831
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
From Serendipity to Scalability in Rare Disease Patient Collaborations
(2025) Missouri Medicine, 122 (1), pp. 53-59.
Grens, K.a , Weisenberg, J.L.b , Ryther, R.C.b , Gabel, H.W.c
a Vice President of the Tatton Brown Rahman Syndrome Community, StanfordvilleNY, United States
b Washington University School of Medicine Division of Pediatric Neurology, Department of Neurology, St. Louis, MO, United States
c Washington University School of Medicine, Department of Neuroscience, St. Louis, MO, United States
Abstract
As the rate of diagnosis for rare disease increases, so does the need to develop scalable solutions to address patient community needs. Drawing upon our experiences in rare intellectual and developmental disability research, advocacy, and treatment, we present two examples of how collaboration between patient groups, clinicians, and investigators at Washington University in St. Louis have generated invaluable resources to accelerate toward treatments. These successful partnerships serve as models for building research and clinical infrastructure for rare diseases. Copyright 2025 by the Missouri State Medical Association.
Document Type: Article
Publication Stage: Final
Source: Scopus
PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors
(2025) Nature Neuroscience, art. no. 596027, .
DeSpenza, T., Jr.a b c d , Kiziltug, E.c e , Allington, G.f g h , Barson, D.G.a b , McGee, S.i , O’Connor, D.j , Robert, S.M.c , Mekbib, K.Y.c g , Nanda, P.g , Greenberg, A.B.W.c , Singh, A.c , Duy, P.Q.a b c , Mandino, F.j , Zhao, S.k , Lynn, A.b , Reeves, B.C.c , Marlier, A.c , Getz, S.A.l , Nelson-Williams, C.c , Shimelis, H.m , Walsh, L.K.m , Zhang, J.c , Wang, W.l , Prina, M.L.l n , OuYang, A.l , Abdulkareem, A.F.l n , Smith, H.c , Shohfi, J.c , Mehta, N.H.g , Dennis, E.g , Reduron, L.R.l , Hong, J.l , Butler, W.g , Carter, B.S.g , Deniz, E.o , Lake, E.M.R.j , Constable, R.T.j , Sahin, M.p , Srivastava, S.p , Winden, K.p , Hoffman, E.J.q r , Carlson, M.a q r , Gunel, M.c , Lifton, R.P.s , Alper, S.L.t u , Jin, S.C.k , Crair, M.C.a , Moreno-De-Luca, A.m u , Luikart, B.W.l n , Kahle, K.T.c g v w
a Interdepartmental Neuroscience Program, Yale School of Medicine, Yale University, New Haven, CT, United States
b Medical Scientist Training Program, Yale School of Medicine, Yale University, New Haven, CT, United States
c Department of Neurosurgery, Yale School of Medicine, Yale University, New Haven, CT, United States
d Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
e Department of Neurosurgery, University of Michigan, Ann Arbor, MI, United States
f Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, United States
g Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
h Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons and New York Presbyterian Hospital, New York, NY, United States
i GeneDx, Gaithersburg, MD, United States
j Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, United States
k Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
l Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
m Autism & Developmental Medicine Institute, Geisinger, Lewisburg, PA, United States
n Department of Neurobiology, UAB Heersink School of Medicine, Birmingham, AL, United States
o Department of Pediatrics, Yale University School of Medicine, New Haven, CT, United States
p Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
q Child Study Center, Yale School of Medicine, New Haven, CT, United States
r Department of Neuroscience, Yale School of Medicine, New Haven, CT, United States
s Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, United States
t Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA, United States
u Department of Radiology, Diagnostic Medicine Institute, Geisinger, Danville, PA, United States
v Broad Institute of Harvard and MIT, Cambridge, MA, United States
w Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, United States
Abstract
Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (ventriculomegaly) is a defining feature of congenital hydrocephalus (CH) and an under-recognized concomitant of autism. Here, we show that de novo mutations in the autism risk gene PTEN are among the most frequent monogenic causes of CH and primary ventriculomegaly. Mouse Pten-mutant ventriculomegaly results from aqueductal stenosis due to hyperproliferation of periventricular Nkx2.1+ neural progenitor cells (NPCs) and increased CSF production from hyperplastic choroid plexus. Pten-mutant ventriculomegalic cortices exhibit network dysfunction from increased activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or postnatal everolimus treatment corrects ventriculomegaly, rescues cortical deficits and increases survival by antagonizing mTORC1-dependent Nkx2.1+ NPC pathology. Thus, PTEN mutations concurrently alter CSF dynamics and cortical networks by dysregulating Nkx2.1+ NPCs. These results implicate a nonsurgical treatment for CH, demonstrate a genetic association of ventriculomegaly and ASD, and help explain neurodevelopmental phenotypes refractory to CSF shunting in select individuals with CH. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.
Funding details
Hydrocephalus AssociationHA
March of Dimes FoundationMDF
Simons FoundationSF
National Institute of Neurological Disorders and StrokeNINDSF31NS115519
National Institute of Neurological Disorders and StrokeNINDS
National Institute of Mental HealthNIMHT32GM007205, 1R01MH097949
National Institute of Mental HealthNIMH
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDR01HD104938, R01NS127879
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
National Institutes of HealthNIH1R01NS111029-01A1, 1R01NS109358-01
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
N-glycosylation in the SERPIN domain of the C1-esterase inhibitor in hereditary angioedema
(2025) JCI Insight Open Access, Volume 10, Issue 424 February 2025 Article number e185548
Ren, Zhena; Bao, Johna; Zhao, Shuangxiab; Pozzi, Nicolac; Wedner, H. Jamesa; Atkinson, John P.d
a Department of Medicine, Division of Allergy and Immunology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Molecular Diagnostics and Endocrinology, Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
c Department of Biochemistry and Molecular Biology, Edward A. Doisy Research Center, Saint Louis University School of Medicine, St. Louis, MO, United States
d Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Hereditary angioedema is an autosomal dominant disorder caused by defects in C1-esterase inhibitor (C1-INH), resulting in poorly controlled activation of the kallikrein-kinin system and bradykinin overproduction. C1-INH is a heavily glycosylated protein in the serine protease inhibitor (SERPIN) family, yet the role of these glycosylation sites remains unclear. To elucidate the functional impact of N-glycosylation in the SERPIN domain of C1-INH, we engineered 4 sets consisting of 26 variants at or near the N-linked sequon (NXS/T). Among these, 6 are reported in patients with hereditary angioedema and 5 are known C1-INH variants without accessible clinical histories. We systematically evaluated their expression, structure, and functional activity with C1s̄, FXIIa, and kallikrein. Our findings showed that of the 11 reported variants, 7 were deleterious. Deleting N at the 3 naturally occurring N-linked sequons (N238, N253, and N352) resulted in pathologic consequences. Altering these sites by substituting N with A disrupted N-linked sugar attachment, but preserved protein expression and function. Furthermore, an additional N-linked sugar generated at N272 impaired C1-INH function. These findings highlight the importance of N-linked sequons in modulating the expression and function of C1-INH. Insights gained from identifying the pathological consequences of N-glycan variants should assist in defining more tailored therapy. © 2025, Ren et al.
Funding details
Institute of Clinical and Translational SciencesICTS
National Center for Advancing Translational SciencesNCATS
National Institutes of HealthNIHR35 GM136352-01
National Institutes of HealthNIH
Georgia Clinical and Translational Science AllianceGaCTSAUL1TR002345
Georgia Clinical and Translational Science AllianceGaCTSA
Document Type: Article
Publication Stage: Final
Source: Scopus