Tissue-type plasminogen activator is an extracellular mediator of Purkinje cell damage and altered gait

Elisa Cops, Maithili Sashindranath, Maria Daglas, Kieran Matthew Short, Candida da Fonseca Pereira, Terence Pang, Roger Lijnen, Ian Macleod Smyth, Anthony J Hannan, Andre Laval Samson, Robert Lindsay Medcalf

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Abstract

Purkinje neurons are a sensitive and specialised cell type important for fine motor movement and coordination. Purkinje cell damage manifests as motor incoordination and ataxia - a prominent feature of many human disorders including spinocerebellar ataxia and Huntington s disease. A correlation between Purkinje degeneration and excess cerebellar levels of tissue-type plasminogen activator (tPA) has been observed in multiple genetically-distinct models of ataxia. Here we show that Purkinje loss in a mouse model of Huntington s disease also correlates with a 200 increase in cerebellar tPA activity. That elevated tPA levels arise in a variety of ataxia models suggests that tPA is a common mediator of Purkinje damage. To address the specific contribution of tPA to cerebellar dysfunction we studied the T4 mice line that overexpresses murine tPA in postnatal neurons through the Thy1.2 gene promoter, which directs preferential expression to Purkinje cells within the cerebellum. Here we show that T4 mice develop signs of cerebellar damage within 10. weeks of birth including atrophy of Purkinje cell soma and dendrites, astrogliosis, reduced molecular layer volume and altered gait. In contrast, T4 mice displayed no evidence of microgliosis, nor any changes in interneuron density, nor alteration in the cerebellar granular neuron layer. Thus, excess tPA levels may be sufficient to cause targeted Purkinje cell degeneration and ataxia. We propose that elevated cerebellar tPA levels exert a common pathway of Purkinje cell damage. Therapeutically lowering cerebellar tPA levels may represent a novel means of preserving Purkinje cell integrity and motor coordination across a wide range of neurodegenerative diseases. ? 2013 Elsevier Inc.
Original languageEnglish
Pages (from-to)8 - 19
Number of pages12
JournalExperimental Neurology
Volume249C
DOIs
Publication statusPublished - 2013

Cite this

Cops, Elisa ; Sashindranath, Maithili ; Daglas, Maria ; Short, Kieran Matthew ; Pereira, Candida da Fonseca ; Pang, Terence ; Lijnen, Roger ; Smyth, Ian Macleod ; Hannan, Anthony J ; Samson, Andre Laval ; Medcalf, Robert Lindsay. / Tissue-type plasminogen activator is an extracellular mediator of Purkinje cell damage and altered gait. In: Experimental Neurology. 2013 ; Vol. 249C. pp. 8 - 19.
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abstract = "Purkinje neurons are a sensitive and specialised cell type important for fine motor movement and coordination. Purkinje cell damage manifests as motor incoordination and ataxia - a prominent feature of many human disorders including spinocerebellar ataxia and Huntington s disease. A correlation between Purkinje degeneration and excess cerebellar levels of tissue-type plasminogen activator (tPA) has been observed in multiple genetically-distinct models of ataxia. Here we show that Purkinje loss in a mouse model of Huntington s disease also correlates with a 200 increase in cerebellar tPA activity. That elevated tPA levels arise in a variety of ataxia models suggests that tPA is a common mediator of Purkinje damage. To address the specific contribution of tPA to cerebellar dysfunction we studied the T4 mice line that overexpresses murine tPA in postnatal neurons through the Thy1.2 gene promoter, which directs preferential expression to Purkinje cells within the cerebellum. Here we show that T4 mice develop signs of cerebellar damage within 10. weeks of birth including atrophy of Purkinje cell soma and dendrites, astrogliosis, reduced molecular layer volume and altered gait. In contrast, T4 mice displayed no evidence of microgliosis, nor any changes in interneuron density, nor alteration in the cerebellar granular neuron layer. Thus, excess tPA levels may be sufficient to cause targeted Purkinje cell degeneration and ataxia. We propose that elevated cerebellar tPA levels exert a common pathway of Purkinje cell damage. Therapeutically lowering cerebellar tPA levels may represent a novel means of preserving Purkinje cell integrity and motor coordination across a wide range of neurodegenerative diseases. ? 2013 Elsevier Inc.",
author = "Elisa Cops and Maithili Sashindranath and Maria Daglas and Short, {Kieran Matthew} and Pereira, {Candida da Fonseca} and Terence Pang and Roger Lijnen and Smyth, {Ian Macleod} and Hannan, {Anthony J} and Samson, {Andre Laval} and Medcalf, {Robert Lindsay}",
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Tissue-type plasminogen activator is an extracellular mediator of Purkinje cell damage and altered gait. / Cops, Elisa; Sashindranath, Maithili; Daglas, Maria; Short, Kieran Matthew; Pereira, Candida da Fonseca; Pang, Terence; Lijnen, Roger; Smyth, Ian Macleod; Hannan, Anthony J; Samson, Andre Laval; Medcalf, Robert Lindsay.

In: Experimental Neurology, Vol. 249C, 2013, p. 8 - 19.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Tissue-type plasminogen activator is an extracellular mediator of Purkinje cell damage and altered gait

AU - Cops, Elisa

AU - Sashindranath, Maithili

AU - Daglas, Maria

AU - Short, Kieran Matthew

AU - Pereira, Candida da Fonseca

AU - Pang, Terence

AU - Lijnen, Roger

AU - Smyth, Ian Macleod

AU - Hannan, Anthony J

AU - Samson, Andre Laval

AU - Medcalf, Robert Lindsay

PY - 2013

Y1 - 2013

N2 - Purkinje neurons are a sensitive and specialised cell type important for fine motor movement and coordination. Purkinje cell damage manifests as motor incoordination and ataxia - a prominent feature of many human disorders including spinocerebellar ataxia and Huntington s disease. A correlation between Purkinje degeneration and excess cerebellar levels of tissue-type plasminogen activator (tPA) has been observed in multiple genetically-distinct models of ataxia. Here we show that Purkinje loss in a mouse model of Huntington s disease also correlates with a 200 increase in cerebellar tPA activity. That elevated tPA levels arise in a variety of ataxia models suggests that tPA is a common mediator of Purkinje damage. To address the specific contribution of tPA to cerebellar dysfunction we studied the T4 mice line that overexpresses murine tPA in postnatal neurons through the Thy1.2 gene promoter, which directs preferential expression to Purkinje cells within the cerebellum. Here we show that T4 mice develop signs of cerebellar damage within 10. weeks of birth including atrophy of Purkinje cell soma and dendrites, astrogliosis, reduced molecular layer volume and altered gait. In contrast, T4 mice displayed no evidence of microgliosis, nor any changes in interneuron density, nor alteration in the cerebellar granular neuron layer. Thus, excess tPA levels may be sufficient to cause targeted Purkinje cell degeneration and ataxia. We propose that elevated cerebellar tPA levels exert a common pathway of Purkinje cell damage. Therapeutically lowering cerebellar tPA levels may represent a novel means of preserving Purkinje cell integrity and motor coordination across a wide range of neurodegenerative diseases. ? 2013 Elsevier Inc.

AB - Purkinje neurons are a sensitive and specialised cell type important for fine motor movement and coordination. Purkinje cell damage manifests as motor incoordination and ataxia - a prominent feature of many human disorders including spinocerebellar ataxia and Huntington s disease. A correlation between Purkinje degeneration and excess cerebellar levels of tissue-type plasminogen activator (tPA) has been observed in multiple genetically-distinct models of ataxia. Here we show that Purkinje loss in a mouse model of Huntington s disease also correlates with a 200 increase in cerebellar tPA activity. That elevated tPA levels arise in a variety of ataxia models suggests that tPA is a common mediator of Purkinje damage. To address the specific contribution of tPA to cerebellar dysfunction we studied the T4 mice line that overexpresses murine tPA in postnatal neurons through the Thy1.2 gene promoter, which directs preferential expression to Purkinje cells within the cerebellum. Here we show that T4 mice develop signs of cerebellar damage within 10. weeks of birth including atrophy of Purkinje cell soma and dendrites, astrogliosis, reduced molecular layer volume and altered gait. In contrast, T4 mice displayed no evidence of microgliosis, nor any changes in interneuron density, nor alteration in the cerebellar granular neuron layer. Thus, excess tPA levels may be sufficient to cause targeted Purkinje cell degeneration and ataxia. We propose that elevated cerebellar tPA levels exert a common pathway of Purkinje cell damage. Therapeutically lowering cerebellar tPA levels may represent a novel means of preserving Purkinje cell integrity and motor coordination across a wide range of neurodegenerative diseases. ? 2013 Elsevier Inc.

UR - http://www.sciencedirect.com/science/article/pii/S0014488613002410

U2 - 10.1016/j.expneurol.2013.08.001

DO - 10.1016/j.expneurol.2013.08.001

M3 - Article

VL - 249C

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JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

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