Cerebellar pathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouse.
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 S100beta 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.
Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Shannon L
SL
Macauley
David F
DF
Wozniak
Catherine
C
Kielar
Yun
Y
Tan
Jonathan D
JD
Cooper
Mark S
MS
Sands
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000235:genetics; D009069:Movement Disorders / Q000235:genetics* / Q000503:physiopathology; D009410:Nerve Degeneration / Q000473:pathology; D009414:Nerve Growth Factors / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000235:genetics; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D013194:Staining and Labeling / Q000379:methods; D013869:Thiolester Hydrolases / Q000172:deficiency*
D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C493393:Slc1a3 protein, mouse; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase