Neuroinflammatory and oxidative stress phenomena in MPS IIIA mouse model: The positive effect of long-term aspirin treatment

Innovative Therapeutic Approaches for Improving Patient Life Condition with a Neurological Lysosomal Disease

“…The observation that the increase of these mediators was accompanied by progressive microglial activation and expansion supports the hypothesis that inflammation is the major cause of neurodegeneration in gangliosidoses. This microglial activation is a characteristic shared by numerous neurodegenerative diseases (Minagar et al, 2002) and other lysosomal diseases, such as MPS I, MPS IIIB (Ohmi et al, 2003), Niemann-Pick type C (German et al, 2002), Krabbe disease (Wu et al, 2000), MPS VII (Richard et al, 2008) and MPS IIIA (Arfi et al, 2011).…”

“…Astrocytosis, like microglial activation, has also been widely described in neurodegenerative disorders (Wu and Proia, 2004;Tsuji et al, 2005;Arfi et al, 2011) and could be triggered by the release from activated macrophages of several cytokines and neurotrophic factors, such as MIP1α and IL1β (Giulian et al, 1988,Wang andShuaib, 2002). …”

“…Other studies previously highlighted the realease of reactive oxygen species (ROS) and/or the increased expression of components of the phagocyte NADPH oxidase in GM1 gangliosidosis (Jeyakumar et al, 2003), MPS IIIB (Villani et al, 2007), MPS I (Reolon et al, 2009), Batten disease (Benedict et al, 2007), or MPS IIIA (Arfi et al, 2011). It is still not defined whether the previously reported and presently observed oxidative imbalance is triggered by lysosomal dysfunction (Butler and Bahr, 2006), by autophagy impairment as recently described in MPS IIIA and Multiple Sulfatase Deficiency mouse models (Settembre et al, 2008), or is a secondary result from microglial activation.…”

Possible diagnostic markers for Mucopolysaccharidoses; Cathepsin-D, Galectin-3 and Chitotriosidase

“…Some authors showed a link between the intralysosomal glycosaminoglycan accumulation and inflammatory process in animal models of MPS IIIA, MPS VI and VII (10,11) . Simoaro et al (11) demonstrated that glycosaminoglycan accumulation leads to release of cytokines, chemokines, proteases and nitric oxide from lysosomes of mice with MPS VI and VII.…”

“…Ohmi et al (12) observed microglia activation due to glycosaminoglycan accumulation in lysosomes in mouse models of MPS I and IIIB. Accumulated heparin and heparan sulfate in the brain of MPS III mice might either directly activate microglia or play a role in activation of microglia through stimulating macrophages (10) . It has been suggested that microglial activation and astroglial activation led to macrophage activation resulting in the release of chemokines and cytokines, which are responsible mediators in neurodegenerative processes.…”