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Islam MI, Nagakannan P, Shcholok T, et al. Regulatory role of cathepsin L in induction of nuclear laminopathy in Alzheimer's disease. Aging Cell. 2021;21(1):e13531doi: 10.1111/acel.13531.
Islam, M. I., Nagakannan, P., Shcholok, T., Contu, F., Mai, S., Albensi, B. C., Del Bigio, M. R., Wang, J. F., Sharoar, M. G., Yan, R., Park, I. S., & Eftekharpour, E. (2022). Regulatory role of cathepsin L in induction of nuclear laminopathy in Alzheimer's disease. Aging cell, 21(1), e13531. https://doi.org/10.1111/acel.13531
Islam, Md Imamul, et al. "Regulatory role of cathepsin L in induction of nuclear laminopathy in Alzheimer's disease." Aging cell vol. 21,1 (2022): e13531. doi: https://doi.org/10.1111/acel.13531
Islam MI, Nagakannan P, Shcholok T, Contu F, Mai S, Albensi BC, Del Bigio MR, Wang JF, Sharoar MG, Yan R, Park IS, Eftekharpour E. Regulatory role of cathepsin L in induction of nuclear laminopathy in Alzheimer's disease. Aging Cell. 2022 Jan;21(1):e13531. doi: 10.1111/acel.13531. Epub 2021 Dec 14. PMID: 34905652.
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Aging Cell. 2022 Jan;21(1):e13531. doi: 10.1111/acel.13531. Epub 2021 Dec 14.

Regulatory role of cathepsin L in induction of nuclear laminopathy in Alzheimer's disease.

Aging cell

Md Imamul Islam, Pandian Nagakannan, Tetiana Shcholok, Fabio Contu, Sabine Mai, Benedict C Albensi, Marc R Del Bigio, Jun-Feng Wang, Md Golam Sharoar, Riqiang Yan, Il-Seon Park, Eftekhar Eftekharpour

Affiliations

  1. Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.
  2. Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
  3. Cell Biology, Research Institute of Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.
  4. St Boniface Hospital, Albrechtsen Research Centre, Winnipeg, MB, Canada.
  5. Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, Florida, USA.
  6. Department of Pathology, Shared Health Manitoba, University of Manitoba, Winnipeg, MB, Canada.
  7. Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada.
  8. Department of Neuroscience, University of Connecticut Health, Farmington, Connecticut, USA.
  9. Department of Cellular and Molecular Medicine, Chosun University, Gwangju, South Korea.

PMID: 34905652 DOI: 10.1111/acel.13531

Abstract

Experimental and clinical therapies in the field of Alzheimer's disease (AD) have focused on elimination of extracellular amyloid beta aggregates or prevention of cytoplasmic neuronal fibrillary tangles formation, yet these approaches have been generally ineffective. Interruption of nuclear lamina integrity, or laminopathy, is a newly identified concept in AD pathophysiology. Unraveling the molecular players in the induction of nuclear lamina damage may lead to identification of new therapies. Here, using 3xTg and APP/PS1 mouse models of AD, and in vitro model of amyloid beta42 (Aβ42) toxicity in primary neuronal cultures and SH-SY5Y neuroblastoma cells, we have uncovered a key role for cathepsin L in the induction of nuclear lamina damage. The applicability of our findings to AD pathophysiology was validated in brain autopsy samples from patients. We report that upregulation of cathepsin L is an important process in the induction of nuclear lamina damage, shown by lamin B1 cleavage, and is associated with epigenetic modifications in AD pathophysiology. More importantly, pharmacological targeting and genetic knock out of cathepsin L mitigated Aβ42 induced lamin B1 degradation and downstream structural and molecular changes. Affirming these findings, overexpression of cathepsin L alone was sufficient to induce lamin B1 cleavage. The proteolytic activity of cathepsin L on lamin B1 was confirmed using mass spectrometry. Our research identifies cathepsin L as a newly identified lamin B1 protease and mediator of laminopathy observed in AD. These results uncover a new aspect in the pathophysiology of AD that can be pharmacologically prevented, raising hope for potential therapeutic interventions.

© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

Keywords: acetylation; amyloid beta; chromatin; histone; lysosomal membrane permeabilization; methylation; nuclear lamina; super-resolution microscopy

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