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

Disease Models & Mechanisms

Pasi Tavi¹  Yajuvinder Singh¹  Jari Koistinaho¹  Henna Konttinen¹  Virve Kärkkäinen¹  Laura Mediavilla Santos¹  Nikolay Naumenko¹  Katja M. Kanninen¹  Velta Keksa-Goldsteine¹  Tarja Malm¹  Ekaterina Savchenko¹  Katarina Lejavova¹  Anthony R. White²  Alexandra Grubman³ 

[1] A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland;Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Herston 4006, Australia;Department of Pathology, University of Melbourne, Parkville 3010, Australia;

关键词: Neurogenesis;    Neuronal ceroid lipofuscinoses;    Batten disease;    Lysosomal storage disease;    Stem cells;    CLN5;   

DOI  :  10.1242/dmm.029165

来源: DOAJ

【 摘 要 】

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 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.

【 授权许可】

Unknown