Sudha Seshadri

Sep 8, 2024 | nature.com | Shahzad Ahmad |Aniket Mishra |Marisol Herrera-Rivero |Joshua C. Bis |Myriam Fornage |Gennady V Roshchupkin | +13 more

AbstractNeurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders.

Jun 11, 2024 | nature.com | Serafima Dubnov |Nadav Yayon |Or Yakov |David Bennett |Sudha Seshadri |Elliott J. Mufson | +7 more

Overexpression of the longevity gene Klotho prolongs lifespan, while its knockout shortens lifespan and impairs cognition via perturbation of myelination and synapse formation. However, comprehensive analysis of Klotho knockout effects on mammalian brain transcriptomics is lacking. Here, we report that Klotho knockout alters the levels of aging- and cognition related mRNAs, long non-coding RNAs, microRNAs and tRNA fragments. These include altered neuronal and glial regulators in murine models of aging and Alzheimer’s disease and in human Alzheimer’s disease post-mortem brains. We further demonstrate interaction of the knockout-elevated tRNA fragments with the spliceosome, possibly affecting RNA processing. Last, we present cell type-specific short RNA-seq datasets from FACS-sorted neurons and microglia of live human brain tissue demonstrating in-depth cell-type association of Klotho knockout-perturbed microRNAs. Together, our findings reveal multiple RNA transcripts in both neurons and glia from murine and human brain that are perturbed in Klotho deficiency and are aging- and neurodegeneration-related. Transcriptomic profiling shows that Klotho knockout perturbs brain short non-coding RNAs, such as microRNA and tRNA fragments, in both neurons and glia, that mimics the changes associated with Alzheimer’s disease and aging in humans and murine models.

Apr 17, 2023 | nature.com | Marie-Gabrielle Duperron |Maria J. Knol |Quentin Le Grand |Tavia E. Evans |Ami Tsuchida |Gennady V Roshchupkin | +35 more

AbstractPerivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter.

Feb 9, 2023 | nature.com | Itziar de Rojas |Najada Stringa |Anna Zettergren |Rebecca Sims |Céline Bellenguez |Miguel Calero | +79 more

Author notesThese authors contributed equally: Itziar de Rojas, Sonia Moreno-Grau, Niccolo Tesi, Benjamin Grenier-Boley, Victor Andrade, Iris E. Jansen. These authors jointly supervised this work: Jordi Clarimón, Mercè Boada, Wiesje M. van der Flier, Alfredo Ramirez, Jean-Charles Lambert, Sven J. van der Lee, Agustín Ruiz.