Journal Article

Loss of Cln5 causes altered neurogenesis in a mouse model of a childhood neurodegenerative disorder

Konttinen, Henna, Lejavova, Katarina, Malm, Tarja, Tavi, Pasi, Kanninen, Katja M, Savchenko, Ekaterina, Kärkkäinen, Virve, Singh, Yajuvinder, Mediavilla Santos, Laura, White, Anthony R, Keksa-Goldsteine, Velta, Koistinaho, Jari, Grubman, Alexandra, Naumenko, Nikolay

2017

Overview

Neural 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 Our findings demonstrate a newly identified crucial role for CLN5 in neurogenesis. We report for the first time that neurogenesis is increased in -deficient mice, which model the childhood neurodegenerative disorder caused by loss of Our results demonstrate that, in 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.

• Publisher: The Company of Biologists Ltd,The Company of Biologists
• Subject: Age / Aging / Alzheimer's disease / Animals / Apoptosis / Apoptosis - drug effects / Batten disease / Brain / Calcium - metabolism / Cell Differentiation - drug effects / Cell growth / Cell Movement - drug effects / Cell Proliferation - drug effects / Child / Childhood / CLN5 / Disease Models, Animal / Genotype & phenotype / Growth factors / Hippocampus - metabolism / Hippocampus - pathology / Humans / Interleukin-1beta - pharmacology / Labeling / Lysosomal Membrane Proteins / Lysosomal storage disease / Membrane Glycoproteins - deficiency / Membrane Glycoproteins - genetics / Membrane Glycoproteins - metabolism / Mice, Inbred C57BL / Mice, Knockout / Neural Stem Cells - drug effects / Neural Stem Cells - metabolism / Neurogenesis / Neurogenesis - drug effects / Neuronal ceroid lipofuscinoses / Neuronal Ceroid-Lipofuscinoses - metabolism / Neuronal Ceroid-Lipofuscinoses - pathology / Phenotype / Proteins / RNA, Messenger - genetics / RNA, Messenger - metabolism / Statistical analysis / Statistical methods / Stem cells