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VERSION:2.0
PRODID:icalendar-ruby
CALSCALE:GREGORIAN
X-WR-CALNAME:Characterizing Genetic and Therapeutic Modulators of TDP-43 Ag
 gregation
X-WR-TIMEZONE:Eastern Time (US & Canada)
BEGIN:VEVENT
DTSTAMP:20260814T011001Z
UID:tag:localist.com\,2008:EventInstance_53189083980861
DTSTART:20260709T180000Z
DTEND:20260709T200000Z
DESCRIPTION:Marilyn Ngo\, MPH - Final Dissertation Defense - HUGEN PhD Cand
 idate\n\n \n\nDepartment of Human Genetics Doctoral Candidate\, Marilyn Ng
 o\, MPH\, will defend the following dissertation on “Characterizing Gene
 tic and Therapeutic Modulators of TDP-43 Aggregation”\n\n \n\nCOMMITTEE 
 CHAIR: Christopher J. Donnelly\, PhD\n\nCommittee Members:\n\nJulia K. Kof
 ler\, MDRyan L. Minster\, PhD\, MSISZsolt Urban\, PhD \n\nABSTRACT:\n\n   
        TDP-43 is a DNA/RNA binding protein involved in RNA splicing\, meta
 bolism\, and trafficking. TDP-43 is mislocalized from the nucleus to the c
 ytoplasm where it forms pathological insoluble inclusions through liquid-l
 iquid phase separation (LLPS) in several neurodegenerative diseases includ
 ing Limbic-predominant\, Age-related TDP-43 Encephalopathy (LATE)\, Amyotr
 ophic Lateral Sclerosis (ALS)\, and Frontotemporal Lobar Degeneration (FTL
 D-TDP). \n\n          There are currently 3 FDA-approved therapeutics for 
 ALS and none for FTLD or LATE. Current treatments available for patients e
 xtend survival time and improve quality of life\; however\, none are curat
 ive or target underlying pathological processes of TDP-43 proteinopathies.
  To address this\, we performed a blinded\, two-platform phenotypic screen
  to identify potential small molecule inhibitors of TDP-43 aggregation. Us
 ing a biochemical LLPS assay and an optogenetics-based imaging screen we t
 ested 471 compounds and converged upon a lead compound candidate that lowe
 red both TDP-43 aggregate size and count by ~20%.\n\n          By better u
 nderstanding the genetic landscape of these complex diseases\, we may be a
 ble to further develop targeted therapeutics and enhance precision medicin
 e. To identify genetic modifiers of TDP-43 proteinopathies\, we performed 
 a genome-wide association study looking for modulators of TDP-43 aggregati
 on on a postmortem cohort of moderate to severe Alzheimer’s disease (AD)
  cases with variable presence of concurrent LATE pathology and identified 
 a genome-wide significant signal in SCY1 Like Pseudokinase 3 (SCYL3\; rs73
 026223). This variant was associated with increased severity of TDP-43 pat
 hology in a 3-tiered staging system (p=3.61E-08) and correlated with decre
 ased SCYL3 expression based on GTEx data. Functional studies demonstrated 
 that knocking down SCYL3 expression promotes aberrant TDP-43 LLPS\, sugges
 ting a role for SCYL3 in TDP-43 pathology.\n\n          To further explore
  the mechanisms by which SCYL3 may influence TDP-43 pathobiology\, we char
 acterized the SCYL3-dependent transcriptomic landscape and protein interac
 tome using RNA sequencing in human iPSC-derived motor neurons and APEX2-ba
 sed proximity labeling. These approaches implicate cytoskeletal organizati
 on and ROCK-associated signaling networks as candidate pathways through wh
 ich SCYL3 may influence neuronal structure and signaling. This work highli
 ghts how SCYL3 is a potential genetic modifier that may contribute to sele
 ctive neuronal vulnerability in TDP-43 proteinopathies.\n\n \n\nIN-PERSON 
 EVENT - ALL WELCOME
GEO:40.442859;-79.958417
LOCATION:School of Public Health\, A115 Public Health
SUMMARY:Characterizing Genetic and Therapeutic Modulators of TDP-43 Aggrega
 tion
URL;VALUE=URI:https://calendar.pitt.edu/event/characterizing-genetic-and-th
 erapeutic-modulators-of-tdp-43-aggregation
CATEGORIES:Defenses
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END:VCALENDAR