TY - JOUR
T1 - Purkinje-cell-specific DNA repair-deficient mice reveal that dietary restriction protects neurons by cell-intrinsic preservation of genomic health
AU - Birkisdóttir, María Björk
AU - Van’t Sant, Lisanne J.
AU - Brandt, Renata M. C.
AU - Barnhoorn, Sander
AU - Hoeijmakers, Jan H. J.
AU - Vermeij, Wilbert P.
AU - Jaarsma, Dick
N1 - Copyright © 2023 Birkisdóttir, Van’t Sant, Brandt, Barnhoorn, Hoeijmakers, Vermeij and Jaarsma.
PY - 2023/1/24
Y1 - 2023/1/24
N2 - Dietary restriction (DR) is a universal anti-aging intervention, which reduces age-related nervous system pathologies and neurological decline. The degree to which the neuroprotective effect of DR operates by attenuating cell intrinsic degradative processes rather than influencing non-cell autonomous factors such as glial and vascular health or systemic inflammatory status is incompletely understood. Following up on our finding that DR has a remarkably large beneficial effect on nervous system pathology in whole-body DNA repair-deficient progeroid mice, we show here that DR also exerts strong neuroprotection in mouse models in which a single neuronal cell type, i.e., cerebellar Purkinje cells, experience genotoxic stress and consequent premature aging-like dysfunction. Purkinje cell specific hypomorphic and knock-out ERCC1 mice on DR retained 40 and 25% more neurons, respectively, with equal protection against P53 activation, and alike results from whole-body ERCC1-deficient mice. Our findings show that DR strongly reduces Purkinje cell death in our Purkinje cell-specific accelerated aging mouse model, indicating that DR protects Purkinje cells from intrinsic DNA-damage-driven neurodegeneration.
AB - Dietary restriction (DR) is a universal anti-aging intervention, which reduces age-related nervous system pathologies and neurological decline. The degree to which the neuroprotective effect of DR operates by attenuating cell intrinsic degradative processes rather than influencing non-cell autonomous factors such as glial and vascular health or systemic inflammatory status is incompletely understood. Following up on our finding that DR has a remarkably large beneficial effect on nervous system pathology in whole-body DNA repair-deficient progeroid mice, we show here that DR also exerts strong neuroprotection in mouse models in which a single neuronal cell type, i.e., cerebellar Purkinje cells, experience genotoxic stress and consequent premature aging-like dysfunction. Purkinje cell specific hypomorphic and knock-out ERCC1 mice on DR retained 40 and 25% more neurons, respectively, with equal protection against P53 activation, and alike results from whole-body ERCC1-deficient mice. Our findings show that DR strongly reduces Purkinje cell death in our Purkinje cell-specific accelerated aging mouse model, indicating that DR protects Purkinje cells from intrinsic DNA-damage-driven neurodegeneration.
KW - DNA damage
KW - DNA repair
KW - Progeria
KW - Purkinje neurons
KW - cerebellum
KW - dietary restriction
KW - nucleotide excision repair
KW - transcription stress
UR - https://pubmed.ncbi.nlm.nih.gov/36760711/
UR - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9902592/
UR - https://www.mendeley.com/catalogue/32ba2aba-717c-3da5-ac03-e6fe373ddbec/
U2 - 10.3389/fnagi.2022.1095801
DO - 10.3389/fnagi.2022.1095801
M3 - Article
C2 - 36760711
SN - 1663-4365
VL - 14
SP - 1095801
JO - Frontiers in Aging Neuroscience
JF - Frontiers in Aging Neuroscience
ER -