TY - JOUR
T1 - Metformin promotes CNS remyelination and improves social interaction following focal demyelination through CBP Ser436 phosphorylation
AU - Kosaraju, Jayasankar
AU - Seegobin, Matthew
AU - Gouveia, Ayden
AU - Syal, Charvi
AU - Sarma, Sailendra Nath
AU - Lu, Kevin Jiaqi
AU - Ilin, Julius
AU - He, Ling
AU - Wondisford, Fredric E.
AU - Lagace, Diane
AU - De Repentigny, Yves
AU - Kothary, Rashmi
AU - Wang, Jing
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/12
Y1 - 2020/12
N2 - Individuals with demyelinating diseases often experience difficulties during social interactions that are not well studied in preclinical models. Here, we describe a novel juvenile focal corpus callosum demyelination murine model exhibiting a social interaction deficit. Using this preclinical murine demyelination model, we discover that application of metformin, an FDA-approved drug, in this model promotes oligodendrocyte regeneration and remyelination and improves the social interaction. This beneficial effect of metformin acts through stimulating Ser436 phosphorylation in CBP, a histone acetyltransferase. In addition, we found that metformin acts through two distinct molecular pathways to enhance oligodendrocyte precursor (OPC) proliferation and differentiation, respectively. Metformin enhances OPC proliferation through early-stage autophagy inhibition, while metformin promotes OPC differentiation into mature oligodendrocytes through activating CBP Ser436 phosphorylation. In summary, we identify that metformin is a promising remyelinating agent to improve juvenile demyelination-associated social interaction deficits by promoting oligodendrocyte regeneration and remyelination.
AB - Individuals with demyelinating diseases often experience difficulties during social interactions that are not well studied in preclinical models. Here, we describe a novel juvenile focal corpus callosum demyelination murine model exhibiting a social interaction deficit. Using this preclinical murine demyelination model, we discover that application of metformin, an FDA-approved drug, in this model promotes oligodendrocyte regeneration and remyelination and improves the social interaction. This beneficial effect of metformin acts through stimulating Ser436 phosphorylation in CBP, a histone acetyltransferase. In addition, we found that metformin acts through two distinct molecular pathways to enhance oligodendrocyte precursor (OPC) proliferation and differentiation, respectively. Metformin enhances OPC proliferation through early-stage autophagy inhibition, while metformin promotes OPC differentiation into mature oligodendrocytes through activating CBP Ser436 phosphorylation. In summary, we identify that metformin is a promising remyelinating agent to improve juvenile demyelination-associated social interaction deficits by promoting oligodendrocyte regeneration and remyelination.
KW - CBP S436 phosphorylation
KW - Differentiation
KW - Mature oligodendrocytes
KW - Metformin
KW - Myelin
KW - Oligodendrocyte precursors
KW - Social interaction
KW - White matter demyelinating disease
UR - http://www.scopus.com/inward/record.url?scp=85090120218&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85090120218&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2020.113454
DO - 10.1016/j.expneurol.2020.113454
M3 - Article
C2 - 32877653
AN - SCOPUS:85090120218
SN - 0014-4886
VL - 334
JO - Experimental Neurology
JF - Experimental Neurology
M1 - 113454
ER -