Cerebellar pathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouse

Shannon L. Macauley; David F. Wozniak; Catherine Kielar; Yun Tan; Jonathan D. Cooper; Mark S. Sands

doi:10.1016/j.expneurol.2009.01.022

Cerebellar pathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouse

Shannon L. Macauley, David F. Wozniak, Catherine Kielar, Yun Tan, Jonathan D. Cooper, Mark S. Sands

Research output: Contribution to journal › Article › peer-review

66 Scopus citations

Abstract

Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten Disease) is an inherited, neurodegenerative lysosomal storage disorder. INCL is the result of a CLN1 gene mutation leading to a deficiency in palmitoyl protein thioesterase 1 (PPT1) activity. Studies in the forebrain demonstrate the PPT1-deficient mouse (PPT1-/-) mimics the clinical symptoms and underlying pathology of INCL; however, little is known about changes in cerebellar function or pathology. In this study, we demonstrate Purkinje cell loss beginning at 3 months, which correlates with changes in rotarod performance. Concurrently, we observed an early stage reactive gliosis and a primary pathology in astrocytes, including changes in S100β and GLAST expression. Conversely, there was a late stage granule cell loss, microglial activation, and demyelination. This study suggests that neuronal-glial interactions are the core pathology in the PPT1-/- cerebellum. In addition, these data identify potential endpoints for use in future efficacy studies for the treatment of INCL.

Original language	English
Pages (from-to)	124-135
Number of pages	12
Journal	Experimental Neurology
Volume	217
Issue number	1
DOIs	https://doi.org/10.1016/j.expneurol.2009.01.022
State	Published - May 2009

Bibliographical note

Funding Information:
We would like to thank Neuroscience Associates (Knoxville, TN) for their consistent quality of silver degeneration staining. This work was supported by NIH grants (NS043105; MSS and NS41930; JDC), Ruth L. Kirschstein NRSA Fellowship (NS056728; SLM), grant support and a graduate studentship from the Batten Disease Support and Research Association (CK), and an NIH Neuroscience Blueprint Core Grant (P30 NS057105; DFW) to Washington University.

Keywords

Astrocytes
Batten disease
Cerebellar mutant
GLAST
Gliosis
Glutamine synthetase
Lysosomal storage disease
Neurodegeneration
Rotarod
Silver degeneration staining

ASJC Scopus subject areas

Neurology
Developmental Neuroscience

Access to Document

10.1016/j.expneurol.2009.01.022

Cite this

@article{4acf64fec42b452581b5057047b40672,

title = "Cerebellar pathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouse",

abstract = "Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten Disease) is an inherited, neurodegenerative lysosomal storage disorder. INCL is the result of a CLN1 gene mutation leading to a deficiency in palmitoyl protein thioesterase 1 (PPT1) activity. Studies in the forebrain demonstrate the PPT1-deficient mouse (PPT1-/-) mimics the clinical symptoms and underlying pathology of INCL; however, little is known about changes in cerebellar function or pathology. In this study, we demonstrate Purkinje cell loss beginning at 3 months, which correlates with changes in rotarod performance. Concurrently, we observed an early stage reactive gliosis and a primary pathology in astrocytes, including changes in S100β and GLAST expression. Conversely, there was a late stage granule cell loss, microglial activation, and demyelination. This study suggests that neuronal-glial interactions are the core pathology in the PPT1-/- cerebellum. In addition, these data identify potential endpoints for use in future efficacy studies for the treatment of INCL.",

keywords = "Astrocytes, Batten disease, Cerebellar mutant, GLAST, Gliosis, Glutamine synthetase, Lysosomal storage disease, Neurodegeneration, Rotarod, Silver degeneration staining",

author = "Macauley, {Shannon L.} and Wozniak, {David F.} and Catherine Kielar and Yun Tan and Cooper, {Jonathan D.} and Sands, {Mark S.}",

note = "Funding Information: We would like to thank Neuroscience Associates (Knoxville, TN) for their consistent quality of silver degeneration staining. This work was supported by NIH grants (NS043105; MSS and NS41930; JDC), Ruth L. Kirschstein NRSA Fellowship (NS056728; SLM), grant support and a graduate studentship from the Batten Disease Support and Research Association (CK), and an NIH Neuroscience Blueprint Core Grant (P30 NS057105; DFW) to Washington University.",

year = "2009",

month = may,

doi = "10.1016/j.expneurol.2009.01.022",

language = "English",

volume = "217",

pages = "124--135",

number = "1",

}

TY - JOUR

T1 - Cerebellar pathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouse

AU - Macauley, Shannon L.

AU - Wozniak, David F.

AU - Kielar, Catherine

AU - Tan, Yun

AU - Cooper, Jonathan D.

AU - Sands, Mark S.

N1 - Funding Information: We would like to thank Neuroscience Associates (Knoxville, TN) for their consistent quality of silver degeneration staining. This work was supported by NIH grants (NS043105; MSS and NS41930; JDC), Ruth L. Kirschstein NRSA Fellowship (NS056728; SLM), grant support and a graduate studentship from the Batten Disease Support and Research Association (CK), and an NIH Neuroscience Blueprint Core Grant (P30 NS057105; DFW) to Washington University.

PY - 2009/5

Y1 - 2009/5

N2 - Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten Disease) is an inherited, neurodegenerative lysosomal storage disorder. INCL is the result of a CLN1 gene mutation leading to a deficiency in palmitoyl protein thioesterase 1 (PPT1) activity. Studies in the forebrain demonstrate the PPT1-deficient mouse (PPT1-/-) mimics the clinical symptoms and underlying pathology of INCL; however, little is known about changes in cerebellar function or pathology. In this study, we demonstrate Purkinje cell loss beginning at 3 months, which correlates with changes in rotarod performance. Concurrently, we observed an early stage reactive gliosis and a primary pathology in astrocytes, including changes in S100β and GLAST expression. Conversely, there was a late stage granule cell loss, microglial activation, and demyelination. This study suggests that neuronal-glial interactions are the core pathology in the PPT1-/- cerebellum. In addition, these data identify potential endpoints for use in future efficacy studies for the treatment of INCL.

AB - Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten Disease) is an inherited, neurodegenerative lysosomal storage disorder. INCL is the result of a CLN1 gene mutation leading to a deficiency in palmitoyl protein thioesterase 1 (PPT1) activity. Studies in the forebrain demonstrate the PPT1-deficient mouse (PPT1-/-) mimics the clinical symptoms and underlying pathology of INCL; however, little is known about changes in cerebellar function or pathology. In this study, we demonstrate Purkinje cell loss beginning at 3 months, which correlates with changes in rotarod performance. Concurrently, we observed an early stage reactive gliosis and a primary pathology in astrocytes, including changes in S100β and GLAST expression. Conversely, there was a late stage granule cell loss, microglial activation, and demyelination. This study suggests that neuronal-glial interactions are the core pathology in the PPT1-/- cerebellum. In addition, these data identify potential endpoints for use in future efficacy studies for the treatment of INCL.

KW - Astrocytes

KW - Batten disease

KW - Cerebellar mutant

KW - GLAST

KW - Gliosis

KW - Glutamine synthetase

KW - Lysosomal storage disease

KW - Neurodegeneration

KW - Rotarod

KW - Silver degeneration staining

UR - http://www.scopus.com/inward/record.url?scp=64549084081&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=64549084081&partnerID=8YFLogxK

U2 - 10.1016/j.expneurol.2009.01.022

DO - 10.1016/j.expneurol.2009.01.022

M3 - Article

C2 - 19416667

AN - SCOPUS:64549084081

SN - 0014-4886

VL - 217

SP - 124

EP - 135

JO - Experimental Neurology

JF - Experimental Neurology

IS - 1

ER -

Cerebellar pathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouse

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this