Neuroinflammatory paradigms in lysosomal storage diseases

Abstract

Lysosomal storage diseases (LSDs) include approximately 70 distinct disorders that collectively account for 14% of all inherited metabolic diseases. LSDs are caused by mutations in various enzymes/proteins that disrupt lysosomal function, which impairs macromolecule degradation following endosome-lysosome and phagosome-lysosome fusion and autophagy, ultimately disrupting cellular homeostasis. LSDs are pathologically typified by lysosomal inclusions composed of a heterogeneous mixture of various proteins and lipids that can be found throughout the body. However, in many cases the CNS is dramatically affected, which may result from heightened neuronal vulnerability based on their post-mitotic state. Besides intrinsic neuronal defects, another emerging factor common to many LSDs is neuroinflammation, which may negatively impact neuronal survival and contribute to neurodegeneration. Microglial and astrocyte activation is a hallmark of many LSDs that affect the CNS, which often precedes and predicts regions where eventual neuron loss will occur. However, the timing, intensity, and duration of neuroinflammation may ultimately dictate the impact on CNS homeostasis. For example, a transient inflammatory response following CNS insult/injury can be neuroprotective, as glial cells attempt to remove the insult and provide trophic support to neurons. However, chronic inflammation, as seen in several LSDs, can promote neurodegeneration by creating a neurotoxic environment due to elevated levels of cytokines, chemokines, and pro-apoptotic molecules. Although neuroinflammation has been reported in several LSDs, the cellular basis and mechanisms responsible for eliciting neuroinflammatory pathways are just beginning to be defined. This review highlights the role of neuroinflammation in select LSDs and its potential contribution to neuron loss.

Lipid‐induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders

“…Microglia alterations could promote neuronal dysfunction in various neurodegenerative disorders (Perry et al, 2010;Bosch & Kielian, 2015). In contrast, microglia play beneficial roles in prion-induced neurodegeneration (Zhu et al, 2016) or amyotrophic lateral sclerosis (Spiller et al, 2018).…”

Predominant role of microglia in brain iron retention in Sanfilippo syndrome, a pediatric neurodegenerative disease

“…It is well known that activated microglia contribute to the neuroinflammatory process (Cunningham, 2013;Tang & Le, 2016). These primary innate immune responder cells sense pathogens or neural injury through a variety of signaling pathways (including the Toll-like receptor, TLR), and then release proinflammatory cytokines such as interleukin IL-1b, IL-6, and tumor necrosis factor (TNF-a) (Bosch & Kielian, 2015;R eus et al, 2015;Tang & Le, 2016). Although the cellular distribution of iron in the brain is well documented (Ward, Zucca, Duyn, Crichton, & Zecca, 2014), the involvement of each brain cell type and the mechanism underlying iron accumulation are subject to debate.…”

Rosmarinic Acid Attenuates the Activation of Murine Microglial N9 Cells through the Downregulation of Inflammatory Cytokines and Cleaved Caspase-3

“…They play a role in the surveillance, maintenance, protection, and restoration of nervous system homeostasis [12,13] . Under stress conditions that might pose a risk to neuronal survival, microglial cells can be activated by cytokines produced by the infiltration of immune effector cells after CNS injury, or by lipopolysaccharides (LPS) during bacterial infection [14,15] .…”