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.
Macauley
Shannon L
SL
Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Wozniak
David F
DF
Kielar
Catherine
C
Tan
Yun
Y
Cooper
Jonathan D
JD
Sands
Mark S
MS
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