Late onset neurodegeneration in the Cln3−/− mouse model of juvenile neuronal ceroid lipofuscinosis is preceded by low level glial activation

Pontikis, Charlie C.; Cella, Claire V.; Parihar, Nisha; Lim, Ming; Chakrabarti, Shubhodeep; Mitchison, Hannah M.; Mobley, William C.; Rezaie, Payam; Pearce, David A.; Cooper, Jonathan D.

doi:10.1016/j.brainres.2004.07.030

Cited by 140 publications

(208 citation statements)

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“…Another feature of JNCL is neuronal loss, which is more limited in Cln3 mouse models compared to human disease 7, 52. A prior publication reported thalamic neuron loss in Cln3 Δex7/8 mice on a mixed 129Sv/Ev/CD1 background at 12 months7; however, this reduction was relatively modest and we have not observed any differences in neuron counts of Nissl‐stained sections in a 1 in 6 series using unbiased stereology between vehicle‐treated WT and Cln3 Δex7/8 animals on a C57BL/6 background, which is known to harbor milder disease phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of phosphodiesterase‐4 inhibitors in juvenile Batten disease (CLN3)

Aldrich

Bosch

Fallet

et al. 2016

Annals of Neurology

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ObjectiveJuvenile neuronal ceroid lipofuscinosis (JNCL), or juvenile Batten disease, is a pediatric lysosomal storage disease caused by autosomal recessive mutations in CLN3, typified by blindness, seizures, progressive cognitive and motor decline, and premature death. Currently, there is no treatment for JNCL that slows disease progression, which highlights the need to explore novel strategies to extend the survival and quality of life of afflicted children. Cyclic adenosine monophosphate (cAMP) is a second messenger with pleiotropic effects, including regulating neuroinflammation and neuronal survival. Here we investigated whether 3 phosphodiesterase‐4 (PDE4) inhibitors (rolipram, roflumilast, and PF‐06266047) could mitigate behavioral deficits and cell‐specific pathology in the Cln3Δex7/8 mouse model of JNCL.MethodsIn a randomized, blinded study, wild‐type (WT) and Cln3Δex7/8 mice received PDE4 inhibitors daily beginning at 1 or 3 months of age and continuing for 6 to 9 months, with motor deficits assessed by accelerating rotarod testing. The effect of PDE4 inhibitors on cAMP levels, astrocyte and microglial activation (glial fibrillary acidic protein and CD68, respectively), lysosomal pathology (lysosomal‐associated membrane protein 1), and astrocyte glutamate transporter expression (glutamate/aspartate transporter) were also examined in WT and Cln3Δex7/8 animals.ResultscAMP levels were significantly reduced in the Cln3Δex7/8 brain, and were restored by PF‐06266047. PDE4 inhibitors significantly improved motor function in Cln3Δex7/8 mice, attenuated glial activation and lysosomal pathology, and restored glutamate transporter expression to levels observed in WT animals, with no evidence of toxicity as revealed by blood chemistry analysis.InterpretationThese studies reveal neuroprotective effects for PDE4 inhibitors in Cln3Δex7/8 mice and support their therapeutic potential in JNCL patients. Ann Neurol 2016;80:909–923

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Section: Discussionmentioning

confidence: 99%

Efficacy of phosphodiesterase‐4 inhibitors in juvenile Batten disease (CLN3)

Aldrich

Bosch

Fallet

et al. 2016

Annals of Neurology

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“…The low affinity, soluble form is predominately expressed within astrocytes of the brain, where as the MB-COMT is primarily found in neurons (Rivett et al, 1983a, b). Although neuroanatomical analysis has failed to reveal any volumetric decrease in the striatum of Cln3 -/-mice, by five months of age there is an elevation in both reactive astrocytes and microglia within this compartment, indicative of on-going cellular damage and targeted cellular stress within the striatum (Pontikis et al, 2004).…”

Section: Disruption In Key Enzyme Involved In Catecholamine Catabolismentioning

confidence: 94%

“…Recent attempts to elucidate the events leading up to cell loss and microglial activation in the Cln3 -/-mice have demonstrated elevated oxidative burden in different anatomical compartments, often with activated microglial located immediately adjacent to neurons reactive for potent antioxidant markers (Benedict et al, 2007). Elevated oxidative stress within the striatum could result from or trigger the previously reported inflammatory response (Pontikis et al, 2004), subsequently leading to restricted cellular changes, including the post-synaptic receptor down regulation reported in JNCL (Rinne et al, 2002). Indeed, we saw a marked increase in oxidized proteins and the down regulation of D1α receptors in the Cln3 -/-striatum by nine months of age, paralleling the increase in glial activation.…”

Section: Introductionmentioning

confidence: 98%

“…Although NCL mouse models have shown many similar pathological characteristic as patients Seigel et al, 2002;Sappington et al, 2003;Pontikis et al, 2004;Pontikis et al, 2005;Kielar et al, 2007), neuroanatomical analysis of the Cln3 -/-mice has failed to reveal any regional volumetric changes of the striatum, although detailed analysis of target cell loss in this area has not been performed (Pontikis et al, 2004). Interestingly, in the Cln3 -/-mice, as well as other NCL models, there is a marked increase in the levels of both reactive astrocytes and microglia within this compartment, indicative of cellular damage (Pontikis et al, 2004;Pontikis et al, 2005;Kielar et al, 2007). Interestingly, gene expression studies of the Cln3 -/-mouse brain have uncovered a marked decrease in the expression of catechol-O-methyl transferase (COMT) (Elshatory et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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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.

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“…26,29 Briefly, 40 non-overlapping images were captured on 4 consecutive sections spanning the injection site of NILV/ ILV within the forebrain. Images were captured with a live video camera (JVC, 3CCD, KY-F55B), mounted onto a Zeiss Axioplan microscope using a Â 40 objective.…”

Section: Quantitative Analysis Of Lentiviral Expression In Adult Micementioning

confidence: 99%

Efficient gene delivery to the adult and fetal CNS using pseudotyped non-integrating lentiviral vectors

et al. 2009

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Non-integrating lentiviral vectors show considerable promise for gene therapy applications as they persist as long-term episomes in non-dividing cells and diminish risks of insertional mutagenesis. In this study, non-integrating lentiviral vectors were evaluated for their use in the adult and fetal central nervous system of rodents. Vectors differentially pseudotyped with vesicular stomatitis virus, rabies and baculoviral envelope proteins allowed targeting of varied cell populations. Efficient gene delivery to discrete areas of the brain and spinal cord was observed following stereotactic administration. Furthermore, after direct in utero administration (E14), sustained and strong expression was observed 4 months into adulthood. Quantification of transduction and viral copy number was comparable when using nonintegrating lentivirus and conventional integrating vector. These data support the use of non-integrating lentiviral vectors as an effective alternative to their integrating counterparts in gene therapy applications, and highlight their potential for treatment of inherited and acquired neurological disorders.

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Late onset neurodegeneration in the Cln3−/− mouse model of juvenile neuronal ceroid lipofuscinosis is preceded by low level glial activation

Cited by 140 publications

References 38 publications

Efficacy of phosphodiesterase‐4 inhibitors in juvenile Batten disease (CLN3)

Efficacy of phosphodiesterase‐4 inhibitors in juvenile Batten disease (CLN3)

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

Efficient gene delivery to the adult and fetal CNS using pseudotyped non-integrating lentiviral vectors

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