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
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 -