Brain gene expression profiles of Cln1 and Cln5 deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases

Carina Von Schantz,Jonathan D Cooper,Outi Kopra,Anu Jalanko,Juha Saharinen,Massimiliano Gentile,Iiris Hovatta,Leena Peltonen

doi:10.1186/1471-2164-9-146

Abstract

BackgroundThe neuronal ceroid lipofuscinoses (NCL) are a group of children's inherited neurodegenerative disorders, characterized by blindness, early dementia and pronounced cortical atrophy. The similar pathological and clinical profiles of the different forms of NCL suggest that common disease mechanisms may be involved. To explore the NCL-associated disease pathology and molecular pathways, we have previously produced targeted knock-out mice for Cln1 and Cln5. Both mouse-models replicate the NCL phenotype and neuropathology; the Cln1-/- model presents with early onset, severe neurodegenerative disease, whereas the Cln5-/- model produces a milder disease with a later onset.ResultsHere we have performed quantitative gene expression profiling of the cortex from 1 and 4 month old Cln1-/- and Cln5-/- mice. Combined microarray datasets from both mouse models exposed a common affected pathway: genes regulating neuronal growth cone stabilization display similar aberrations in both models. We analyzed locus specific gene expression and showed regional clustering of Cln1 and three major genes of this pathway, further supporting a close functional relationship between the corresponding gene products; adenylate cyclase-associated protein 1 (Cap1), protein tyrosine phosphatase receptor type F (Ptprf) and protein tyrosine phosphatase 4a2 (Ptp4a2). The evidence from the gene expression data, indicating changes in the growth cone assembly, was substantiated by the immunofluorescence staining patterns of Cln1-/- and Cln5-/- cortical neurons. These primary neurons displayed abnormalities in cytoskeleton-associated proteins actin and β-tubulin as well as abnormal intracellular distribution of growth cone associated proteins GAP-43, synapsin and Rab3.ConclusionOur data provide the first evidence for a common molecular pathogenesis behind neuronal degeneration in INCL and vLINCL. Since CLN1 and CLN5 code for proteins with distinct functional roles these data may have implications for other forms of NCLs as well.

Highlights

The neuronal ceroid lipofuscinoses (NCL) are a group of children's inherited neurodegenerative disorders, characterized by blindness, early dementia and pronounced cortical atrophy
The precise mechanisms by which mutations in these genes result in a dramatic neuronal degeneration are still unknown, but the broadly similar pathological and clinical profiles of the different NCLs suggest that common molecular pathways might link these diseases together, despite having a differing primary cause
We have addressed the global changes in transcript profiles in the cerebral cortex of the Cln1-/- and Cln5-/- mice with the hypothesis that this would provide us with clues of critical metabolic pathways that contribute to the neurological phenotype and neuronal degeneration

Summary

Introduction

The neuronal ceroid lipofuscinoses (NCL) are a group of children's inherited neurodegenerative disorders, characterized by blindness, early dementia and pronounced cortical atrophy. To explore the NCL-associated disease pathology and molecular pathways, we have previously produced targeted knock-out mice for Cln and Cln. To explore the NCL-associated disease pathology and molecular pathways, we have previously produced targeted knock-out mice for Cln and Cln5 Both mouse-models replicate the NCL phenotype and neuropathology; the Cln1-/- model presents with early onset, severe neurodegenerative disease, whereas the Cln5-/- model produces a milder disease with a later onset. The precise mechanisms by which mutations in these genes result in a dramatic neuronal degeneration are still unknown, but the broadly similar pathological and clinical profiles of the different NCLs suggest that common molecular pathways might link these diseases together, despite having a differing primary cause. CLN5 is shown to interact both with the CLN3 and the CLN2 proteins [19]

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