SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex

Acta Neuropathologica Communications

Research

Andrés M. Baraibar¹  Michael K. Lee²  Mathew A. Sherman²  Minwoo Kim²  Samuel Boes²  Damyan W. Hart²  Michelle Sung³  Gabriel E. Boyle⁴  Michael LaCroix⁵  Taylor G. Brown⁶  Alfonso Araque⁷  Jennifer L. Brown⁸  Ross Pelzel⁸  Sylvain E. Lesné⁸  Tracy Cole⁹ 

[1] Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA;Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa, Spain;Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA;Institute for Translational Neuroscience, University of Minnesota, Wallin Medical Biosciences Building (Room 4-114), 2101 Sixth Street SE, CDC 2641, 55414, Minneapolis, MN, USA;Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA;Institute for Translational Neuroscience, University of Minnesota, Wallin Medical Biosciences Building (Room 4-114), 2101 Sixth Street SE, CDC 2641, 55414, Minneapolis, MN, USA;Bloomberg School of Public Health, Johns Hopkins University, 21218, Baltimore, MD, USA;Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA;Institute for Translational Neuroscience, University of Minnesota, Wallin Medical Biosciences Building (Room 4-114), 2101 Sixth Street SE, CDC 2641, 55414, Minneapolis, MN, USA;Graduate Program in Molecular and Cellular Biology, University of Washington, 98195, Seattle, WA, USA;Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA;Institute for Translational Neuroscience, University of Minnesota, Wallin Medical Biosciences Building (Room 4-114), 2101 Sixth Street SE, CDC 2641, 55414, Minneapolis, MN, USA;Medical Scientist Training Program, University of Texas Southwestern Medical School, 75390, Dallas, TX, USA;Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA;Medical Scientist Training Program, University of Minnesota, Minneapolis, MN, USA;Institute for Translational Neuroscience, University of Minnesota, Wallin Medical Biosciences Building (Room 4-114), 2101 Sixth Street SE, CDC 2641, 55414, Minneapolis, MN, USA;Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA;Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA;Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA;Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA;Institute for Translational Neuroscience, University of Minnesota, Wallin Medical Biosciences Building (Room 4-114), 2101 Sixth Street SE, CDC 2641, 55414, Minneapolis, MN, USA;Ionis Pharmaceuticals Inc., Carlsbad, CA, USA;n-Lorem Foundation, 92010, Carlsbad, CA, USA;

关键词: Alpha-synuclein;    Spatial memory;    Sex;    Antisense oligonucleotide;    Synucleinopathy;    Alzheimer’s disease;    Early growth response 1;   

DOI  :  10.1186/s40478-022-01480-y

 received in 2022-08-23, accepted in 2022-11-18,  发布年份 2022

来源: Springer

【 摘 要 】

Antisense oligonucleotide (ASO) therapy for neurological disease has been successful in clinical settings and its potential has generated hope for Alzheimer’s disease (AD). We previously described that ablating SNCA encoding for α-synuclein (αSyn) in a mouse model of AD was beneficial. Here, we sought to demonstrate whether transient reduction of αSyn expression using ASOSNCA could be therapeutic in a mouse model of AD. The efficacy of the ASOSNCA was measured via immunocytochemistry, RT-qPCR and western blotting. To assess spatial learning and memory, ASOSNCA or PBS-injected APP and non-transgenic (NTG) mice, and separate groups of SNCA-null mice, were tested on the Barnes circular maze. Hippocampal slice electrophysiology and transcriptomic profiling were used to explore synaptic function and differential gene expression between groups. Reduction of SNCA transcripts alleviated cognitive deficits in male transgenic animals, but surprisingly, not in females. To determine the functional cause of this differential effect, we assessed memory function in SNCA-null mice. Learning and memory were intact in male mice but impaired in female animals, revealing that the role of αSyn on cognitive function is sex-specific. Transcriptional analyses identified a differentially expressed gene network centered around EGR1, a central modulator of learning and memory, in the hippocampi of SNCA-null mice. Thus, these novel results demonstrate that the function of αSyn on memory differs between male and female brains.

【 授权许可】

CC BY   
© The Author(s) 2022

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