Abstract
ABSTRACTNeural stem/progenitor cells (NPCs) generate new neurons in the brain throughout an individual's lifetime in an intricate process called neurogenesis. Neurogenic alterations are a common feature of several adult-onset neurodegenerative diseases. The neuronal ceroid lipofuscinoses (NCLs) are the most common group of inherited neurodegenerative diseases that mainly affect children. Pathological features of the NCLs include accumulation of lysosomal storage material, neuroinflammation and neuronal degeneration, yet the exact cause of this group of diseases remains poorly understood. The function of the CLN5 protein, causative of the CLN5 disease form of NCL, is unknown. In the present study, we sought to examine neurogenesis in the neurodegenerative disorder caused by loss of Cln5. Our findings demonstrate a newly identified crucial role for CLN5 in neurogenesis. We report for the first time that neurogenesis is increased in Cln5-deficient mice, which model the childhood neurodegenerative disorder caused by loss of Cln5. Our results demonstrate that, in Cln5 deficiency, proliferation of NPCs is increased, NPC migration is reduced and NPC differentiation towards the neuronal lineage is increased concomitantly with functional alterations in the NPCs. Moreover, the observed impairment in neurogenesis is correlated with increased expression of the pro-inflammatory cytokine IL-1β. A full understanding of the pathological mechanisms that lead to disease and the function of the NCL proteins are critical for designing effective therapeutic approaches for this devastating neurodegenerative disorder.
Highlights
Neurogenesis occurs throughout life in the mammalian brain (Altman, 1962), and is correlated with learning and memory functions
Cln5 deficiency increases hippocampal neurogenesis To assess whether the disease caused by loss of Cln5 is associated with neurogenic alterations in vivo, brains from Cln5-knockout (KO) and wild-type (WT) mice at various ages were processed for immunohistochemistry
These results indicate that Cln5 deficiency alters neurogenesis in a timedependent fashion, and that the number of newly forming precursors and immature neurons is significantly increased in Cln5-KO mice
Summary
Neurogenesis occurs throughout life in the mammalian brain (Altman, 1962), and is correlated with learning and memory functions During this complex process, new neurons are generated in specific neurogenic niches in the brain, including the subgranular zone of the hippocampal dentate gyrus and the subventricular zone. The newly generated neurons are derived from neuronal stem/progenitor cells (NPCs), which proliferate and produce neuronal and glial cells under physiological conditions This dynamic process requires coordinated cell proliferation, apoptosis, migration, differentiation and functional integration. The regulation of neuronal development in the postnatal period is intricate and involves numerous intrinsic and extracellular factors, including growth factors and cytokines (Faigle and Song, 2013)
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