Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms

Mukesh Gautam, Javier H. Jara, Gabriella Sekerkova, Marina V. Yasvoina, Marco Martina, P. Hande Özdinler*

*Corresponding author for this work

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Mutations in the ALS2 gene result in early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary lateral sclerosis, suggesting prominent upper motor neuron involvement. However, the importance of alsin function for corticospinal motor neuron (CSMN) health and stability remains unknown. To date, four separate alsin knockout (AlsinKO) mouse models have been generated, and despite hopes of mimicking human pathology, none displayed profound motor function defects. This, however, does not rule out the possibility of neuronal defects within CSMN, which is not easy to detect in these mice. Detailed cellular analysis of CSMN has been hampered due to their limited numbers and the complex and heterogeneous structure of the cerebral cortex. In an effort to visualize CSMN in vivo and to investigate precise aspects of neuronal abnormalities in the absence of alsin function, we generated AlsinKO-UeGFP mice, by crossing AlsinKO and UCHL1-eGFP mice, a CSMN reporter line. We find that CSMN display vacuolated apical dendrites with increased autophagy, shrinkage of soma size and axonal pathology even in the pons region. Immunocytochemistry coupled with electron microscopy reveal that alsin is important for maintaining cellular cytoarchitecture and integrity of cellular organelles. In its absence, CSMN displays selective defects both in mitochondria and Golgi apparatus. UCHL1-eGFP mice help understand the underlying cellular factors that lead to CSMN vulnerability in diseases, and our findings reveal unique importance of alsin function for CSMN health and stability.

Original languageEnglish (US)
Pages (from-to)1074-1087
Number of pages14
JournalHuman molecular genetics
Volume25
Issue number6
DOIs
StatePublished - Aug 17 2015

Fingerprint

Motor Neurons
Knockout Mice
Hereditary Spastic Paraplegia
Pathology
Pons
Autophagy
Health
Amyotrophic Lateral Sclerosis
Golgi Apparatus
Carisoprodol
Dendrites
Organelles
Cerebral Cortex
Electron Microscopy
Mitochondria
Immunohistochemistry
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

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title = "Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms",
abstract = "Mutations in the ALS2 gene result in early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary lateral sclerosis, suggesting prominent upper motor neuron involvement. However, the importance of alsin function for corticospinal motor neuron (CSMN) health and stability remains unknown. To date, four separate alsin knockout (AlsinKO) mouse models have been generated, and despite hopes of mimicking human pathology, none displayed profound motor function defects. This, however, does not rule out the possibility of neuronal defects within CSMN, which is not easy to detect in these mice. Detailed cellular analysis of CSMN has been hampered due to their limited numbers and the complex and heterogeneous structure of the cerebral cortex. In an effort to visualize CSMN in vivo and to investigate precise aspects of neuronal abnormalities in the absence of alsin function, we generated AlsinKO-UeGFP mice, by crossing AlsinKO and UCHL1-eGFP mice, a CSMN reporter line. We find that CSMN display vacuolated apical dendrites with increased autophagy, shrinkage of soma size and axonal pathology even in the pons region. Immunocytochemistry coupled with electron microscopy reveal that alsin is important for maintaining cellular cytoarchitecture and integrity of cellular organelles. In its absence, CSMN displays selective defects both in mitochondria and Golgi apparatus. UCHL1-eGFP mice help understand the underlying cellular factors that lead to CSMN vulnerability in diseases, and our findings reveal unique importance of alsin function for CSMN health and stability.",
author = "Mukesh Gautam and Jara, {Javier H.} and Gabriella Sekerkova and Yasvoina, {Marina V.} and Marco Martina and {\"O}zdinler, {P. Hande}",
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Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms. / Gautam, Mukesh; Jara, Javier H.; Sekerkova, Gabriella; Yasvoina, Marina V.; Martina, Marco; Özdinler, P. Hande.

In: Human molecular genetics, Vol. 25, No. 6, 17.08.2015, p. 1074-1087.

Research output: Contribution to journalArticle

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AU - Gautam, Mukesh

AU - Jara, Javier H.

AU - Sekerkova, Gabriella

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AU - Martina, Marco

AU - Özdinler, P. Hande

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