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A New Role for Laminins as Modulators of Protein Toxicity in Caenorhabditis elegans

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  • Louise Toft Jensen, Danmark
  • Tine Hørning Møller
  • ,
  • Simon Asbjørn Larsen, Danmark
  • Helle Jakobsen
  • Anders Olsen, Danmark
Protein misfolding is a common theme in aging and several age-related diseases such as Alzheimer's and Parkinson's disease. The processes involved in the development of these diseases are many and complex. Here, we show that components of the basement membrane, particularly laminin, affect protein integrity of the muscle cells they support. We knocked down gene expression of epi-1, a laminin α-chain, and found that this resulted in increased proteotoxicity in different Caenorhabditis elegans transgenic models expressing aggregating proteins in the body wall muscle. The effect could partially be rescued by decreased insulin-like signaling, known to slow the aging process and the onset of various age-related diseases. Our data points to an underlying molecular mechanism involving proteasomal degradation and HSP-16 chaperone activity. Furthermore, epi-1 depleted animals had altered synaptic function and displayed hypersensitivity to both levamisole and aldicarb, an acetylcholine receptor agonist and an acetylcholinesterase inhibitor, respectively. Our results implicate the basement membrane as an extracellular modulator of protein homeostasis in the adjacent muscle cells. This is in agreement with previous research showing that imbalance in neuromuscular signaling disturbs protein homeostasis in the postsynaptic cell. In our study, proteotoxicity may indeed be mediated by the neuromuscular junction which is part of the basement membrane, where laminins are present in high concentration, ensuring the proper microenvironment for neuromuscular signaling. Laminins are evolutionarily conserved and thus the basement membrane may play a much more causal role in protein misfolding diseases than currently recognized. © 2011 The Authors Aging Cell© 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
OriginalsprogEngelsk
TidsskriftAging Cell
Vol/bind11
Nummer1
Sider (fra-til)82-92
ISSN1474-9718
DOI
StatusUdgivet - feb. 2012

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