Hyaluronan Synthesis, Catabolism, and Signaling in Neurodegenerative Diseases

Abstract

The glycosaminoglycan hyaluronan (HA), a component of the extracellular matrix, has been implicated in regulating neural differentiation, survival, proliferation, migration, and cell signaling in the mammalian central nervous system (CNS). HA is found throughout the CNS as a constituent of proteoglycans, especially within perineuronal nets that have been implicated in regulating neuronal activity. HA is also found in the white matter where it is diffusely distributed around astrocytes and oligodendrocytes. Insults to the CNS lead to long-term elevation of HA within damaged tissues, which is linked at least in part to increased transcription of HA synthases. HA accumulation is often accompanied by elevated expression of at least some transmembrane HA receptors including CD44. Hyaluronidases that digest high molecular weight HA into smaller fragments are also elevated following CNS insults and can generate HA digestion products that have unique biological activities. A number of studies, for example, suggest that both the removal of high molecular weight HA and the accumulation of hyaluronidase-generated HA digestion products can impact CNS injuries through mechanisms that include the regulation of progenitor cell differentiation and proliferation. These studies, reviewed here, suggest that targeting HA synthesis, catabolism, and signaling are all potential strategies to promote CNS repair.

Brain extracellular space, hyaluronan, and the prevention of epileptic seizures

“…Perhaps most importantly, commercially available hyaluronidases contain other contaminating enzymatic activities, such as chondroitinase and protease; for example, mammalian testicular hyaluronidase preparations invariably possess chondroitinase activity. In addition, exogenous hyaluronidase will create HA digestion products, which themselves can have biological activity (Sherman et al, 2015). Rather than using hyaluronidase, our group took a genetic approach to investigate the role of hyaluronan in the CNS (Arranz et al, 2014).…”

“…While direct application of HA to the brains of epilepsy patients may not be feasible, we could potentially manipulate the balance between endogenous production and degradation of HA. The two obvious ways to regulate the amount of hyaluronic acid are via regulation of HA synthesis (Tammi et al, 2011; Vigetti et al, 2014) or via regulation of hyaluronidase activity (Sherman et al, 2015). …”

“…There is hope that a treatment will be developed which can be administered during the latent period which would stop the process of epileptogenesis and prevent the onset of spontaneous seizures. In analyzing results that suggest that HA may be epileptogenic or antiepileptogenic, it is worth pointing out that the scientific community is lately becoming increasingly aware that both high- and low-molecular-weight HA have biological effects, that those effects are often not the same, and that some studies measuring changes in HA content have not differentiated between HA of different sizes (Cowman et al, 2015; Sherman et al, 2015). …”

“…We know that an initiating insult such as an episode of status epilepticus, ischemia, or mechanical trauma can set off the process of epileptogenesis. In many cases of brain insult, it seems that there is first a reduction and then an increase in high-molecular-weight HA (Sherman et al, 2015). Data indicate that the initial decrease in high-molecular-weight HA may be due either to an increase in HA breakdown or a decrease in HA synthesis, or both.…”

“…Activated AMPK phosphorylates threonine 110 on the cytoplasmic loop of HAS, causing a dramatic inhibition of HAS activity (Vigetti et al, 2014). Sherman et al (2015) suggests that the initial decrease in high-molecular-weight HA that occurs following various CNS injuries may be the key step that should be targeted to promote a better outcome. Following that reasoning and considering the data presented above, we suggest that inhibitors of hyaluronidases, perhaps combined with stimulators of HAS, might prevent epileptogenesis if administered during the latent period.…”