Biomedical subjects

Jill M Weimer

Publications and source records attributed to Jill M Weimer.

7 recordsLinked to original sources

PubMed2006

Selectively increased sensitivity of cerebellar granule cells to AMPA receptor-mediated excitotoxicity in a mouse model of Batten disease.

Batten disease, a lysosomal storage disorder, is caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3-/-) mouse model of the disease exhibits many characteristic pathological features of the human disorder. Here, we show that Cln3-/- mice, similarly to Batten disease patients, have a deficit in cerebellar motor coordination. To explore the possible cellular cause of this functional impairment, we compared the vulnerability of wild type (WT) and Cln3-/- cerebellar granule cell cultures to different toxic insults. We have found that cultured Cln3-/- cerebellar granule cells are selectively more vulnerable to AMPA-type glutamate receptor-mediated toxicity than their WT counterparts. This selective sensitivity was also observed in organotypic cerebellar slice cultures. Our results suggest that lack of the CLN3 protein has a significant influence on the function of AMPA receptors in cerebellar granule neurons, and that AMPA receptor dysregulation may be a major contributor to the cerebellar dysfunction in Batten disease.

Animals↗

PubMed2006

Visual deficits in a mouse model of Batten disease are the result of optic nerve degeneration and loss of dorsal lateral geniculate thalamic neurons.

Juvenile neuronal ceroid lipofuscinosis (JNCL) is an autosomal recessive disorder of childhood caused by mutations in CLN3. Although visual deterioration is typically the first clinical sign to manifest in affected children, loss of Cln3 in a mouse model of JNCL does not recapitulate this retinal deterioration. This suggests that either the loss of CLN3 does not directly affect retinal cell survival or that nuclei involved in visual processing are affected prior to retinal degeneration. Having previously demonstrated that Cln3(-/-) mice have decreased optic nerve axonal density, we now demonstrate a decrease in nerve conduction. Examination of retino-recipient regions revealed a decreased number of neurons within the dorsal lateral geniculate nucleus (LGNd). We demonstrate decreased transport of amino acids from the retina to the LGN, suggesting an impediment in communication between the retina and projection nuclei. This study defines a novel path of degeneration within the LGNd, providing a mechanism for causation of JNCL visual deficits.

Animals↗

PubMed2006

Doubling up on microtubule stabilizers: synergistic functions of doublecortin-like kinase and doublecortin in the developing cerebral cortex.

Dynamic regulation of neuronal cytoskeletal machinery in response to extracellular cues enables distinct changes in neuronal development in the cerebral cortex. In this issue of Neuron, three related studies on doublecortin-like kinase, a microtubule-associated protein related to doublecortin, by Shu et al., Koizumi et al., and Deuel et al., provide evidence that doublecortin-like kinase is essential for proper neurogenesis, neuronal migration, and axonal wiring.

Aging↗

PubMed2005

Novel CLN3 mutation predicted to cause complete loss of protein function does not modify the classical JNCL phenotype.

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), or Batten disease, is a childhood neurodegenerative disease that is characterized clinically by progressive visual loss, seizures, dementia, and motor incoordination. Children affected with this disease tend to develop normally for the first 5 years of life. However, once disease onset occurs, they decline rapidly and die in their late 20s to early 30s. Though this represents the typical disease course, the onset and severity of disease symptoms can vary. This variability is presumed to be the result of both differences in the causative genetic mutation in the CLN3 gene as well as environmental influences. Most cases of JNCL are caused by a 1 kb deletion in the CLN3 gene, resulting in a frameshift mutation predicted to leave the first 153 amino acids of the CLN3 protein intact, followed by the addition of 28 novel amino acids. Here we report the discovery of a novel mutation identified as a G to T transversion at nucleotide 49 (G49T) in exon 2 of CLN3, introducing a premature stop codon (E17X) near the N-terminus. This mutation represents the most 5' mutation described to date. The patient examined in this study was heterozygous for the common 1 kb deletion and E17X. She had classical disease progression, suggesting that this mutation in CLN3 mimics the more prevalent 1 kb deletion and that progression of JNCL is predominantly the result of loss of CLN3 function.

Adult↗

PubMed2005

Elevation of Hook1 in a disease model of Batten disease does not affect a novel interaction between Ankyrin G and Hook1.

Hook1 is a member of a family of microtubule-binding proteins. Studies on the Drosophila homolog of Hook1 have suggested a role in the maturation and trafficking of internalized proteins to the late endosome. A weak interaction between Hook1 and the lysosomal/late endosomal protein, CLN3, was recently reported. Mutations in CLN3 result in the neurological disorder Batten disease. Here we show a novel interaction between Hook1 and Ankyrin G, an adaptor protein that binds the spectrin-actin cytoskeleton and targets proteins to the peripheral membrane. Although we demonstrate co-localization of Hook1 and Ankyrin G, Hook1 also localizes to additional regions of the cell devoid of Ankyrin G where it likely interacts with other proteins. There is no disruption of the Hook1-Ankyrin G interaction or localization in tissue derived from a Cln3-knockout mouse despite a nearly threefold increase in the expression of Hook1. However, mutation of CLN3 could lead to alterations in the functioning and positioning of organelles and membrane proteins through this Hook1-Ankyrin G interaction.

Animals↗

PubMed2005

CLN3, the protein associated with batten disease: structure, function and localization.

Batten disease, an inherited neurodegenerative storage disease affecting children, results from the autosomal recessive inheritance of mutations in Cln3. The function of the CLN3 protein remains unknown. A key to understanding the pathology of this devastating disease will be to elucidate the function of CLN3 at the cellular level. CLN3 has proven difficult to study as it is predicted to be a membrane protein expressed at relatively low levels. This article is a critical review of various approaches used in examining the structure, trafficking, and localization of CLN3. We conclude that CLN3 is likely resident in the lysosomal/endosomal membrane. Different groups have postulated conflicting orientations for CLN3 within this membrane. In addition, CLN3 undergoes several posttranslational modifications and is trafficked through the endoplasmic reticulum and Golgi. Recent evidence also suggests that CLN3 traffics via the plasma membrane. Although the function of this protein remains elusive, it is apparent that genetic alterations in Cln3 may have a direct affect on lysosomal function.

Animals↗

PubMed2002

The neuronal ceroid lipofuscinoses: mutations in different proteins result in similar disease.

The neuronal ceroid-lipofuscinoses (NCL) are the most common group of progressive neurodegenerative diseases in children, with an incidence as high as one in 12,500 live births. The main features of this disease are failure of psychomotor development, impaired vision, seizures, and premature death. Many biochemical and physiological studies have been initiated to determine the cellular defect underlying the disease, although only a few traits have been truly associated with the disorders. One of the paradox's of the NCL-diseases is the characteristic accumulation of autofluorescent hydrophobic material in the lysosomes of neurons and other cell types. However, the accumulation of this lysosomal storage material, which no doubt contributes to the neurologic disease, does not apparently lead to disease outside the CNS, and how these cellular alterations relate to the neurodegeneration in NCLs is unknown. Mutations have been identified in six distinct genes/proteins, namely CLN1, which encodes PPT1, a protein thiolesterase; CLN2, which encodes TPP1, a serine protease; and CLN3, CLN5, CLN6, and CLN8, which encode novel transmembrane proteins. Mutation in any one of these CLN-proteins results in a distinct type of NCL-disease. However, there are many shared similarities in the pathology of these diseases. The most obvious connection between PPT1, TPP1, CLN3, CLN5, CLN6, and CLN8 is their subcellular localization. To date, three of the four proteins whose subcellular localization has been confirmed, namely PPT1, TPP1, and CLN3, reside in the lysosome. We review the function of the CLN-proteins and discuss the possibility that a disruption in a common biological process leads to an NCL-disease.

Child↗