PMID- 37214956
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240119
DP  - 2023 May 9
TI  - Longitudinal modeling of human neuronal aging identifies RCAN1-TFEB pathway 
      contributing to neurodegeneration of Huntington's disease.
LID - rs.3.rs-2815300 [pii]
LID - 10.21203/rs.3.rs-2815300/v1 [doi]
AB  - Aging is a common risk factor in neurodegenerative disorders and the ability to 
      investigate aging of neurons in an isogenic background would facilitate 
      discovering the interplay between neuronal aging and onset of neurodegeneration. 
      Here, we perform direct neuronal reprogramming of longitudinally collected human 
      fibroblasts to reveal genetic pathways altered at different ages. Comparative 
      transcriptome analysis of longitudinally aged striatal medium spiny neurons 
      (MSNs), a primary neuronal subtype affected in Huntington's disease (HD), 
      identified pathways associated with RCAN1, a negative regulator of calcineurin. 
      Notably, RCAN1 undergoes age-dependent increase at the protein level detected in 
      reprogrammed MSNs as well as in human postmortem striatum. In patient-derived 
      MSNs of adult-onset HD (HD-MSNs), counteracting RCAN1 by gene knockdown (KD) 
      rescued HD-MSNs from degeneration. The protective effect of RCAN1 KD was 
      associated with enhanced chromatin accessibility of genes involved in longevity 
      and autophagy, mediated through enhanced calcineurin activity, which in turn 
      dephosphorylates and promotes nuclear localization of TFEB transcription factor. 
      Furthermore, we reveal that G2-115 compound, an analog of glibenclamide with 
      autophagy-enhancing activities, reduces the RCAN1-Calcineurin interaction, 
      phenocopying the effect of RCAN1 KD. Our results demonstrate that RCAN1 is a 
      potential genetic or pharmacological target whose reduction-of-function increases 
      neuronal resilience to neurodegeneration in HD through chromatin reconfiguration.
FAU - Lee, Seong Won
AU  - Lee SW
AUID- ORCID: 0000-0001-8176-9118
AD  - Department of Developmental Biology, Washington University School of Medicine, 
      St. Louis, MO 63110, USA.
FAU - Oh, Young Mi
AU  - Oh YM
AUID- ORCID: 0000-0001-8981-5537
AD  - Department of Developmental Biology, Washington University School of Medicine, 
      St. Louis, MO 63110, USA.
FAU - Victor, Matheus B
AU  - Victor MB
AD  - Department of Brain and Cognitive Sciences, Massachusetts Institute of 
      Technology, Cambridge, MA 02139, USA.
FAU - Strunilin, Ilya
AU  - Strunilin I
AUID- ORCID: 0000-0003-0252-0256
AD  - Department of Developmental Biology, Washington University School of Medicine, 
      St. Louis, MO 63110, USA.
FAU - Chen, Shawei
AU  - Chen S
AD  - Department of Developmental Biology, Washington University School of Medicine, 
      St. Louis, MO 63110, USA.
FAU - Dahiya, Sonika
AU  - Dahiya S
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, MO 63110.
FAU - Dolle, Roland E
AU  - Dolle RE
AD  - Department of Biochemistry, Washington University School of Medicine, St. Louis, 
      MO 63110, USA.
FAU - Pak, Stephen C
AU  - Pak SC
AD  - Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 
      63110, USA.
FAU - Silverman, Gary A
AU  - Silverman GA
AUID- ORCID: 0000-0002-2686-2843
AD  - Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 
      63110, USA.
FAU - Perlmutter, David H
AU  - Perlmutter DH
AD  - Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 
      63110, USA.
FAU - Yoo, Andrew S
AU  - Yoo AS
AUID- ORCID: 0000-0002-0304-3247
AD  - Department of Developmental Biology, Washington University School of Medicine, 
      St. Louis, MO 63110, USA.
AD  - Center of Regenerative Medicine, Washington University School of Medicine, St. 
      Louis, MO 63110, USA.
LA  - eng
GR  - R01 NS107488/NS/NINDS NIH HHS/United States
GR  - RF1 AG056296/AG/NIA NIH HHS/United States
PT  - Preprint
DEP - 20230509
PL  - United States
TA  - Res Sq
JT  - Research square
JID - 101768035
UIN - Nat Aging. 2023 Dec 8;:. PMID: 38066314
PMC - PMC10197783
EDAT- 2023/05/22 19:11
MHDA- 2023/05/22 19:12
PMCR- 2023/05/19
CRDT- 2023/05/22 12:18
PHST- 2023/05/22 19:11 [pubmed]
PHST- 2023/05/22 19:12 [medline]
PHST- 2023/05/22 12:18 [entrez]
PHST- 2023/05/19 00:00 [pmc-release]
AID - rs.3.rs-2815300 [pii]
AID - 10.21203/rs.3.rs-2815300/v1 [doi]
PST - epublish
SO  - Res Sq [Preprint]. 2023 May 9:rs.3.rs-2815300. doi: 10.21203/rs.3.rs-2815300/v1.