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

Exp Neurol. 2009 May;217(1):124-35. doi: 10.1016/j.expneurol.2009.01.022. Epub 2009 Feb 10.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Animals
  • Apoptosis / genetics
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Cerebellum / pathology*
  • Cerebellum / physiopathology*
  • Disease Models, Animal
  • Excitatory Amino Acid Transporter 1 / metabolism
  • Excitatory Amino Acid Transporter 2 / metabolism
  • Glial Fibrillary Acidic Protein / metabolism
  • In Situ Nick-End Labeling / methods
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / metabolism
  • Microglia / pathology
  • Motor Activity / genetics
  • Movement Disorders / genetics*
  • Movement Disorders / physiopathology
  • Nerve Degeneration / pathology
  • Nerve Growth Factors / metabolism
  • Neuronal Ceroid-Lipofuscinoses / genetics
  • Neuronal Ceroid-Lipofuscinoses / physiopathology
  • Neurons / metabolism
  • Neurons / pathology
  • Organ Size / genetics
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins / metabolism
  • Staining and Labeling / methods
  • Thiolester Hydrolases / deficiency*


  • Excitatory Amino Acid Transporter 1
  • Excitatory Amino Acid Transporter 2
  • Glial Fibrillary Acidic Protein
  • Nerve Growth Factors
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins
  • Slc1a3 protein, mouse
  • Thiolester Hydrolases
  • palmitoyl-protein thioesterase