Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of juvenile neuronal ceroid lipofuscinosis

Abstract

Batten disease, or juvenile neuronal ceroid lipofuscinosis (JNCL), results from mutations in the CLN3 gene. This disorder presents clinically around the age of five years with visual deficits progressing to include seizures, cognitive impairment, motor deterioration, hallucinations, and premature death by the third to forth decade of life. The motor deficits include coordination and gait abnormalities, myoclonic jerks, inability to initiate movements, and spasticity. Previous work from our laboratory has identified an early reduction in catechol-O-methyltransferase (COMT), an enzyme responsible for the efficient degradation of dopamine. Alterations in the kinetics of dopamine metabolism could cause the accumulation of undegraded or unsequestered dopamine leading to the formation of toxic dopamine intermediates. We report an imbalance in the catabolism of dopamine in three month Cln3 -/-mice persisting through nine months of age that may be causal to oxidative damage within the striatum at nine months of age. Combined with the Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript previously reported inflammatory changes and loss of post-synaptic D1α receptors, this could facilitate cell loss in striatal projection regions and underlie a general locomotion deficit that becomes apparent at twelve months of age in Cln3 -/-mice. This study provides evidence for early changes in the kinetics of COMT in the Cln3 -/-mouse striatum, affecting the turnover of dopamine, likely leading to neuron loss and motor deficits. These data provide novel insights into the basis of motor deficits in JNCL and how alterations in dopamine catabolism may result in oxidative damage and localized neuronal loss in this disorder.

The neuronal ceroid lipofuscinoses: the same, but different?

“…However, another plausible explanation for such species-specific effects is that gene defects in the endosomal-lysosomal system impair intracellular trafficking and/or anterograde transport within neurons. This has already been reported in murine NCL [29] and would be expected to have greater effects in a larger and more complex brain, in which the distances for transport are much greater, and the precise requirements for accurate trafficking are more demanding.…”

“…Over the last decade, we have been characterizing each of the available mouse models of NCL, documenting the onset and progression of pathological changes [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and testing the efficacy of a range of therapeutic interventions [35][36][37][38]. Our studies have revealed a number of new and surprising pathological features that are broadly shared by the different forms of NCL, but with subtype-specific differences in the staging of these events and some more pronounced differences between certain forms of NCL.…”

“…The same regions and pathways that exhibit neuron vulnerability display anterograde transport defects [29], an early rearrangement of the presynaptic compartment, altered SNAP (soluble N-ethylmaleimide-sensitive fusion proteinattachment protein)/SNARE (soluble N-ethylmaleimidesensitive fusion protein-attachment protein receptor) formation and synapse elimination before the onset of neuron loss [30,34,42].…”

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) and the Eye

“…The clinical manifestations of vision loss, deteriorating motor function, and seizures likely result from specific biochemical and molecular disruptions in the neuronal and glial cell populations associated with these functions. 50, 95, 96 …”

A Case-controlled Investigation of Pain Experience and Sensory Function in Neuronal Ceroid Lipofuscinosis

“…19,22 This finding is consistent with a prior case series report documenting analgesic response to fentanyl for central pain in an infant sample. 3 Recent research in animal models 23 and human post mortem analyses 24 suggests that glial activation and synaptic pathology (and not accumulation of lipopigments) are predictive of neuron loss in NCL. More specifically, the biology of astrocytes and microglia seem to be compromised in NCL and could therefore be responsible for the degradation of neurons.…”