Kopitar-Jerala 2018 MiP2018
Accumulating evidence support that neuroinflammation is a common feature across neurodegenerative disorders, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), and play a complex role in their pathophysiology. Cystatins are reversible and tight-binding inhibitors of endolysosomal cysteine cathepsins. Cystatin C is expressed in a variety of tissues and its expression and localization was associated with various neurodegenerative pathologies like AD . Mutations in the gene encoding stefin B are present in patients with a form of progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) and several recent studies reported the role of neuroinflammation in the pathology of the disease [2-4].
We demonstrated that stefin B-deficient mice, as well as cystatin C deficient mice, were significantly more sensitive to the lethal lipopolysaccharide (LPS)-induced sepsis due to increased caspase-11 expression . Upon LPS stimulation, stefin B was targeted into the mitochondria, and the lack of stefin B resulted in the increased destabilization of mitochondrial membrane potential and mitochondrial ROS generation. Moreover, we reported decreased IL-10 expression in stefin B deficient macrophages and increased interleukin 10 ( IL-10) expression in stefin B trisomic macrophages. Recently, we determined impaired autophagy in cells and tissue from stefin B deficient mice. It was reported that IL-10 inhibited LPS-induced glycolysis and promoted oxidative phosphorylation. Furthermore, IL-10 suppressed mammalian target of rapamycin (mTOR) activity. In stefin B deficient macrophages we determined increased mTOR activation and decreased mitophagy.
We conclude that the dysregulation of autophagy in stefin B deficient mice is responsible for the increased inflammatory response and neuroinflammation.
Labels: MiParea: mt-Medicine Pathology: Alzheimer's, Neurodegenerative
Organism: Mouse Tissue;cell: Nervous system, Macrophage-derived
Regulation: mt-Membrane potential
Trstenjak–Prebanda M(1), Biasizzo M(1), Maher K(1), Završnik J(1), Brault V(2), Turk B(1), Hérault Y(2), Kopitar-Jerala N(1)
- Dept Biochemistry, Molecular Structural Biology, Jožef Stefan Inst, Ljubljana, Slovenia. - [email protected]
- Inst Génétique Biologie Moléculaire Cellulaire (IGBMC), Univ Strasbourg, France
- Mathews PM, Levy E (2016) Cystatin C in aging and in Alzheimer's disease. Ageing Res Rev 32:38-50
- Kopitar-Jerala N (2015) The Role of Stefin B in Neuro-inflammation. Front Cell Neurosci 9:458
- Maher K, Jerič Kokelj B, Butinar M, Mikhaylov G, Manček-Keber M, Stoka V, Vasiljeva O, Turk B, Grigoryev SA, Kopitar-Jerala N (2014) A role for stefin B (cystatin B) in inflammation and endotoxemia. J Biol Chem 289:31736-50
- Okuneva O, Li Z, Körber I, Tegelberg S, Joensuu T, Tian L, Lehesjoki AE (2016) Brain inflammation is accompanied by peripheral inflammation in Cstb (-/-) mice, a model for progressive myoclonus epilepsy. J Neuroinflammation 13:298.