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CRISPR-Cas9 treatme...
CRISPR-Cas9 treatment partially restores amyloid-β 42/40 in human fibroblasts with the Alzheimer's disease PSEN1 M146L mutation
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- Konstantinidis, Evangelos (författare)
- Uppsala universitet,Geriatrik,Molekylär geriatrik
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- Molisak, Agnieszka (författare)
- Uppsala universitet,Geriatrik,Molekylär geriatrik
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- Perrin, Florian (författare)
- Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Memory Disorders Unit, Charlestown, MA USA.
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- Streubel-Gallasch, Linn (författare)
- Uppsala universitet,Geriatrik,Molekylär geriatrik
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- Fayad, Sarah (författare)
- Uppsala universitet,Geriatrik,Molekylär geriatrik
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- Kim, Daniel Y. (författare)
- Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA.;Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA.;Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA USA.
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- Petri, Karl (författare)
- Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA.;Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA.;Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA USA.;Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA.
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- Aryee, Martin J. (författare)
- Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA.;Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA.;Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA.;Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA.
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- Aguilar, Ximena (författare)
- Uppsala universitet,Geriatrik,Molekylär geriatrik
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- György, Bence (författare)
- Inst Mol & Clin Ophthalmol Basel, Basel, Switzerland.;Univ Basel, Dept Ophthalmol, Basel, Switzerland.
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- Giedraitis, Vilmantas (författare)
- Uppsala universitet,Geriatrik,Molekylär geriatrik
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- Joung, J. Keith (författare)
- Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA.;Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA.;Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA USA.;Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA.
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- Pattanayak, Vikram (författare)
- Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA.;Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA.;Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA USA.;Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA.
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- Essand, Magnus (författare)
- Uppsala universitet,Klinisk immunologi
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- Erlandsson, Anna (författare)
- Uppsala universitet,Geriatrik,Molekylär geriatrik
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- Berezovska, Oksana (författare)
- Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Memory Disorders Unit, Charlestown, MA USA.
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- Ingelsson, Martin (författare)
- Uppsala universitet,Geriatrik,Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada; Univ Toronto, Dept Med, Toronto, ON, Canada; Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada,Molekylär geriatrik
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(creator_code:org_t)
- Elsevier BV, 2022
- 2022
- Engelska.
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Ingår i: Molecular Therapy Nucleic Acids. - : Elsevier BV. - 2162-2531. ; 28, s. 450-461
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Presenilin 1 (PS1) is a central component of γ-secretase, an enzymatic complex involved in the generation of the amyloid-β (Aβ) peptide that deposits as plaques in the Alzheimer’s disease (AD) brain. The M146L mutation in the PS1 gene (PSEN1) leads to an autosomal dominant form of early-onset AD by promoting a relative increase in the generation of the more aggregation-prone Aβ42. This change is evident not only in the brain but also in peripheral cells of mutation carriers. In this study we used the CRISPR-Cas9 system from Streptococcus pyogenes to selectively disrupt the PSEN1M146L allele in human fibroblasts. A disruption of more than 50% of mutant alleles was observed in all CRISPR-Cas9-treated samples, resulting in reduced extracellular Aβ42/40 ratios. Fluorescence resonance energy transfer-based conformation and western blot analyses indicated that CRISPR-Cas9 treatment also affects the overall PS1 conformation and reduces PS1 levels. Moreover, our guide RNA did not lead to any detectable editing at the highest-ranking candidate off-target sites identified by ONE-seq and CIRCLE-seq. Overall, our data support the effectiveness of CRISPR-Cas9 in selectively targeting the PSEN1M146L allele and counteracting the AD-associated phenotype. We believe that this system could be developed into a therapeutic strategy for patients with this and other dominant mutations leading to early-onset AD.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
Nyckelord
- MT
- RNA/DNA editing
- Alzheimer’s disease
- presenilin 1
- amyloid-β
- fibroblasts
- CRISPR-Cas9
- gene editing
- protein conformation
- off-target effects
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Konstantinidis, ...
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Molisak, Agniesz ...
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Perrin, Florian
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Streubel-Gallasc ...
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Fayad, Sarah
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Kim, Daniel Y.
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visa fler...
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Petri, Karl
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Aryee, Martin J.
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Aguilar, Ximena
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György, Bence
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Giedraitis, Vilm ...
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Joung, J. Keith
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Pattanayak, Vikr ...
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Essand, Magnus
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Erlandsson, Anna
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Berezovska, Oksa ...
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Ingelsson, Marti ...
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visa färre...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinsk biotek ...
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och Medicinsk biotek ...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinska och f ...
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och Medicinsk geneti ...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Neurologi
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Molecular Therap ...
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Uppsala universitet