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

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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1089-1100
Number of pages12
JournalDisease Models and Mechanisms
Volume10
Issue number9
DOIs
Publication statusPublished - 1 Sep 2017

Keywords

  • Batten disease
  • CLN5
  • Lysosomal storage disease
  • Neurogenesis
  • Neuronal ceroid lipofuscinoses
  • Stem cells

Cite this

Savchenko, E., Singh, Y., Konttinen, H., Lejavova, K., Santos, L. M., Grubman, A., ... Kanninen, K. M. (2017). Loss of Cln5 causes altered neurogenesis in a mouse model of a childhood neurodegenerative disorder. Disease Models and Mechanisms, 10(9), 1089-1100. https://doi.org/10.1242/dmm.029165
Savchenko, Ekaterina ; Singh, Yajuvinder ; Konttinen, Henna ; Lejavova, Katarina ; Santos, Laura Mediavilla ; Grubman, Alexandra ; Karkkainen, Virve ; Keksa-Goldsteine, Velta ; Naumenko, Nikolay ; Tavi, Pasi ; White, Anthony R. ; Malm, Tarja ; Koistinaho, Jari ; Kanninen, Katja M. / Loss of Cln5 causes altered neurogenesis in a mouse model of a childhood neurodegenerative disorder. In: Disease Models and Mechanisms. 2017 ; Vol. 10, No. 9. pp. 1089-1100.
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abstract = "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.",
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Savchenko, E, Singh, Y, Konttinen, H, Lejavova, K, Santos, LM, Grubman, A, Karkkainen, V, Keksa-Goldsteine, V, Naumenko, N, Tavi, P, White, AR, Malm, T, Koistinaho, J & Kanninen, KM 2017, 'Loss of Cln5 causes altered neurogenesis in a mouse model of a childhood neurodegenerative disorder', Disease Models and Mechanisms, vol. 10, no. 9, pp. 1089-1100. https://doi.org/10.1242/dmm.029165

Loss of Cln5 causes altered neurogenesis in a mouse model of a childhood neurodegenerative disorder. / Savchenko, Ekaterina; Singh, Yajuvinder; Konttinen, Henna; Lejavova, Katarina; Santos, Laura Mediavilla; Grubman, Alexandra; Karkkainen, Virve; Keksa-Goldsteine, Velta; Naumenko, Nikolay; Tavi, Pasi; White, Anthony R.; Malm, Tarja; Koistinaho, Jari; Kanninen, Katja M.

In: Disease Models and Mechanisms, Vol. 10, No. 9, 01.09.2017, p. 1089-1100.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Loss of Cln5 causes altered neurogenesis in a mouse model of a childhood neurodegenerative disorder

AU - Savchenko, Ekaterina

AU - Singh, Yajuvinder

AU - Konttinen, Henna

AU - Lejavova, Katarina

AU - Santos, Laura Mediavilla

AU - Grubman, Alexandra

AU - Karkkainen, Virve

AU - Keksa-Goldsteine, Velta

AU - Naumenko, Nikolay

AU - Tavi, Pasi

AU - White, Anthony R.

AU - Malm, Tarja

AU - Koistinaho, Jari

AU - Kanninen, Katja M

PY - 2017/9/1

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N2 - 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.

AB - 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.

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