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Protein-RNA complexes & ALS: insights from iCLIP
Published on Jul 21, 2017961 Views
Mutations in several RNA binding proteins (RBPs) cause ALS, including TDP43, hnRNPA1, hnRNPA2/B1, FUS and MATRIN3. Disease-causing mutations are most often concentrated within the intrinsically diso
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Protein-RNA complexes & ALS; insights from iCLIP00:00
Linked mechanisms of brain aging and neurodegeneration00:29
Linked genetics and pathology of ALS and FTLD - 101:39
Linked genetics and pathology of ALS and FTLD - 202:27
Splicing of TDP-43-regulated alternative exons in human brain02:34
Alternative splicing affected by aging and/or disease in human brain03:59
Changes in cell-type specific gene expression programmes04:37
Transcriptional hallmarks of human brain agin05:11
Analysis of cell-type specific gene expression upon aging06:06
Neuroinflammation in neurodegeneration06:52
Immunohistochemistry of NeuN-positive cells in the frontal cortex07:13
NeuN-stained image analysis07:35
Analysis of astrocyte and oligodendrocyte-specific genes08:11
Immunohistochemistry of Olig2-positive cells in the frontal cortex09:34
Quantification Olig2-stained images09:41
Linked mechanisms of brain aging and neurodegeneration09:59
Mutations in many RNA-binding proteins cause age-related diseases10:32
Protein-RNA complexes often form membraneless organelles10:51
Paraspeckles are assembled by a long non-coding RNA (lncRNA)12:16
iCLIP: nucleotide-resolution crosslinking and immunoprecipitation12:29
TDP-43 binds to NEAT1 ncRNA12:54
Comparison of TDP-43 binding in FTLD vs. healthy control brain tissue13:41
Occurrence of NEAT1 ncRNA is increased in ALS motor neurons13:50
We studied paraspeckle dynamics during stem cell differentiation14:34
NEAT1 and paraspeckles are induced by differentiation15:04
TDP-43 represses production of the full NEAT1 transcript15:26
TDP-43 binds close to the polyA site in the NEAT1 transcript15:47
TDP-43 promotes formation of the short NEAT1 transcript16:04
Knockout of the internal polyA site allows production of NEAT1v2 - 116:34
Knockout of the internal polyA site allows production of NEAT1v2 - 216:44
Knockdown of TDP-43 allows production of NEAT1v216:49
Paraspeckles partially sequester TDP-43 away from mRNAs - 116:54
Paraspeckles partially sequester TDP-43 away from mRNAs - 217:52
Cells overexpressing TDP-43 exhibit a developmental delay17:52
Cells lacking NEAT1 exhibit a developmental delay17:52
A computational pipeline to monitor the dynamic functions of TDP-4318:21
TDP-43 knockdown induces the ‘differentiated’ pattern of 3’ end mRNA processing18:52
TDP-43 regulates 3’end processing of SOX2 pre-mRNA19:14
TDP-43 is required for expression of SOX2 protein in pluripotent cells19:33
Cross-regulation of TDP-43 and paraspeckles promote a bistable switch19:51
Bistable switches promote cell fate transitions20:30
Summary20:50
Acknowledgement22:12