7 results on '"Tapia, Juan A."'
Search Results
2. Dysregulated Expression of Transposable Elements in TDP-43 M337V Human Motor Neurons That Recapitulate Amyotrophic Lateral Sclerosis In Vitro.
- Author
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Valdebenito-Maturana, Braulio, Rojas-Tapia, Matias Ignacio, Carrasco, Mónica, and Tapia, Juan Carlos
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AMYOTROPHIC lateral sclerosis ,MOTOR neuron diseases ,GENE expression ,MOTOR neurons ,DNA-binding proteins ,INDUCED pluripotent stem cells ,SPINAL cord ,EXTRACELLULAR matrix - Abstract
Amyotrophic lateral sclerosis (ALS) is a disease that progressively annihilates spinal cord motor neurons, causing severe motor decline and death. The disease is divided into familial and sporadic ALS. Mutations in the TAR DNA binding protein 43 (TDP-43) have been involved in the pathological emergence and progression of ALS, although the molecular mechanisms eliciting the disease are unknown. Transposable elements (TEs) and DNA sequences capable of transposing within the genome become dysregulated and transcribed in the presence of TDP-43 mutations. We performed RNA-Seq in human motor neurons (iMNs) derived from induced pluripotent stem cells (iPSCs) from TDP-43 wild-type—iMNs-TDP-43
WT —and mutant—iMNs-TDP-43M337V —genotypes at 7 and 14 DIV, and, with state-of-the-art bioinformatic tools, analyzed whether TDP-43M337V alters both gene expression and TE activity. Our results show that TDP-43M337V induced global changes in the gene expression and TEs levels at all in vitro stages studied. Interestingly, many genetic pathways overlapped with that of the TEs activity, suggesting that TEs control the expression of several genes. TEs correlated with genes that played key roles in the extracellular matrix and RNA processing: all the regulatory pathways affected in ALS. Thus, the loss of TE regulation is present in TDP-43 mutations and is a critical determinant of the disease in human motor neurons. Overall, our results support the evidence that indicates TEs are critical regulatory sequences contributing to ALS neurodegeneration. [ABSTRACT FROM AUTHOR]- Published
- 2022
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3. Activation of Innate and Humoral Immunity in the Peripheral Nervous System of ALS Transgenic Mice
- Author
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Chiu, Isaac M., Phatnani, Hemali, Kuligowski, Michael, Tapia, Juan C., Carrasco, Monica A., Zhang, Ming, Maniatis, Tom, and Carroll, Michael C.
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- 2009
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4. Locus-specific analysis of Transposable Elements during the progression of ALS in the SOD1G93A mouse model.
- Author
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Valdebenito-Maturana, Braulio, Arancibia, Esteban, Riadi, Gonzalo, Tapia, Juan Carlos, and Carrasco, Mónica
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LABORATORY mice ,MOTOR neuron diseases ,AMYOTROPHIC lateral sclerosis ,ANIMAL disease models ,NEURODEGENERATION ,STATISTICAL association ,DISEASE progression - Abstract
Transposable Elements (TEs) are ubiquitous genetic elements with the ability to move within a genome. TEs contribute to a large fraction of the repetitive elements of a genome, and because of their nature, they are not routinely analyzed in RNA-Seq gene expression studies. Amyotrophic Lateral Sclerosis (ALS) is a lethal neurodegenerative disease, and a well-accepted model for its study is the mouse harboring the human SOD1
G93A mutant. In this model, landmark stages of the disease can be recapitulated at specific time points, making possible to understand changes in gene expression across time. While there are several works reporting TE activity in ALS models, they have not explored their activity through the disease progression. Moreover, they have done it at the expense of losing their locus of expression. Depending on their genomic location, TEs can regulate genes in cis and in trans, making locus-specific analysis of TEs of importance in order to understand their role in modulating gene expression. Particularly, the locus-specific role of TEs in ALS has not been fully elucidated. In this work, we analyzed publicly available RNA-Seq datasets of the SOD1G93A mouse model, to understand the locus-specific role of TEs. We show that TEs become up-regulated at the early stages of the disease, and via statistical associations, we speculate that they can regulate several genes, which in turn might be contributing to the genetic dysfunction observed in ALS. [ABSTRACT FROM AUTHOR]- Published
- 2021
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5. Distinct roles for motor neuron autophagy early and late in the SOD1G93A mouse model of ALS.
- Author
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Rudnick, Noam D., Griffey, Christopher J., Guarnieri, Paolo, Gerbino, Valeria, Xueyong Wang, Piersaint, Jason A., Tapia, Juan Carlos, Rich, Mark M., and Maniatis, Tom
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MOTOR neurons ,AMYOTROPHIC lateral sclerosis ,AUTOPHAGY ,MICE ,SUPEROXIDES - Abstract
Mutations in autophagy genes can cause familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of autophagy in ALS pathogenesis is poorly understood, in part due to the lack of cell type-specific manipulations of this pathway in animal models. Using a mouse model of ALS expressing mutant superoxide dismutase 1 (SOD1
G93A ), we showthat motor neurons form large autophagosomes containing ubiquitinated aggregates early in disease progression. To investigate whether this response is protective or detrimental, we generated mice in which the critical autophagy gene Atg7 was specifically disrupted in motor neurons (Atg7 cKO). Atg7 cKO mice were viable but exhibited structural and functional defects at a subset of vulnerable neuromuscular junctions. By crossing Atg7 cKO mice to the SOD1G93A mouse model, we found that autophagy inhibition accelerated early neuromuscular denervation of the tibialis anterior muscle and the onset of hindlimb tremor. Surprisingly, however, lifespan was extended in Atg7 cKO; SOD1G93A double-mutantmice. Autophagy inhibition did not prevent motor neuron cell death, but it reduced glial inflammation and blocked activation of the stress-related transcription factor c-Jun in spinal interneurons. We conclude that motor neuron autophagy is required to maintain neuromuscular innervation early in disease but eventually acts in a non-cell-autonomous manner to promote disease progression. [ABSTRACT FROM AUTHOR]- Published
- 2017
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6. Spatially Resolved Expression of Transposable Elements in Disease and Somatic Tissue with SpatialTE.
- Author
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Valdebenito-Maturana, Braulio, Guatimosim, Cristina, Carrasco, Mónica Alejandra, and Tapia, Juan Carlos
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GENETIC regulation ,AMYOTROPHIC lateral sclerosis ,REGULATOR genes ,TISSUES ,GENE expression - Abstract
Spatial transcriptomics (ST) is transforming the way we can study gene expression and its regulation through position-specific resolution within tissues. However, as in bulk RNA-Seq, transposable elements (TEs) are not being studied due to their highly repetitive nature. In recent years, TEs have been recognized as important regulators of gene expression, and thus, TE expression analysis in a spatially resolved manner could further help to understand their role in gene regulation within tissues. We present SpatialTE, a tool to analyze TE expression from ST datasets and show its application in somatic and diseased tissues. The results indicate that TEs have spatially regulated expression patterns and that their expression profiles are spatially altered in ALS disease, indicating that TEs might perform differential regulatory functions within tissue organs. We have made SpatialTE publicly available as open-source software under an MIT license. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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7. Shared Resistance to Aging and ALS in Neuromuscular Junctions of Specific Muscles.
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Valdez, Gregorio, Tapia, Juan C., Lichtman, Jeff W., Fox, Michael A., and Sanes, Joshua R.
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NEURODEGENERATION , *AMYOTROPHIC lateral sclerosis , *CENTRAL nervous system , *MYONEURAL junction , *NERVE endings , *MOTOR neurons , *AGING - Abstract
Normal aging and neurodegenerative diseases both lead to structural and functional alterations in synapses. Comparison of synapses that are generally similar but respond differently to insults could provide the basis for discovering mechanisms that underlie susceptibility or resistance to damage. Here, we analyzed skeletal neuromuscular junctions (NMJs) in 16 mouse muscles to seek such differences. We find that muscles respond in one of three ways to aging. In some, including most limb and trunk muscles, age-related alterations to NMJs are progressive and extensive during the second postnatal year. NMJs in other muscles, such as extraocular muscles, are strikingly resistant to change. A third set of muscles, including several muscles of facial expression and the external anal sphinter, succumb to aging but not until the third postnatal year. We asked whether susceptible and resistant muscles differed in rostrocaudal or proximodistal position, source of innervation, motor unit size, or fiber type composition. Of these factors, muscle innervation by brainstem motor neurons correlated best with resistance to age-related decline. Finally, we compared synaptic alterations in normally aging muscles to those in a mouse model of amyotrophic lateral sclerosis (ALS). Patterns of resistance and susceptibility were strikingly correlated in the two conditions. Moreover, damage to NMJs in aged muscles correlated with altered expression and distribution of CRMP4a and TDP-43, which are both altered in motor neurons affected by ALS. Together, these results reveal novel structural, regional and molecular parallels between aging and ALS. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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