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SUMMARY:TDP-43 modulates translation of specific mRNAs linked to neurodege
 nerative disease
DTSTART:20190524T100000
DTSTAMP:20260427T225906Z
UID:72dbb119105f0923dd5f05ddc5ee6dcef9eefdd9f285b83e2b28f2f8
CATEGORIES:Conferences - Seminars
DESCRIPTION:Nagammal Neelagandan\, University Medical Center Hamburg-Eppen
 dorf\, Center for Molecular Neurobiology Hamburg\nThe RNA-binding protein 
 TDP-43 is heavily implicated in neurodegenerative disease. Numerous patien
 t mutations in TARDBP\, the gene encoding TDP-43\, combined with data from
  animal and cell-based models\, imply that altered RNA regulation by TDP-4
 3 causes Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Howeve
 r\, underlying mechanisms remain unresolved. Increased cytoplasmic TDP-43 
 levels in diseased neurons suggest a possible role in this cellular compar
 tment. Here\, we examined the impact on translation of overexpressing huma
 n TDP-43 and the TDP-43A315T patient mutant protein in motor neuron-like c
 ells and primary cultures of cortical neurons. In motor-neuron like cells\
 , TDP-43 associates with ribosomes without significantly affecting global 
 translation. However\, ribosome profiling and additional assays revealed e
 nhanced translation and direct binding of Camta1\, Mig12\, and Dennd4a mRN
 As. Overexpressing either wild-type TDP-43 or TDP-43A315T stimulated trans
 lation of Camta1 and Mig12 mRNAs via their 5′UTRs and increased CAMTA1 a
 nd MIG12 protein levels. In contrast\, translational enhancement of Dennd4
 a mRNA required a specific 3′UTR region and was specifically observed wi
 th the TDP-43A315T patient mutant allele. Our data reveal that TDP-43 can 
 function as an mRNA-specific translational enhancer. Moreover\, since CAMT
 A1 and DENND4A are linked to neurodegeneration\, they suggest that this fu
 nction could contribute to disease.
LOCATION:SV 3510 https://plan.epfl.ch/?room=SV3510
STATUS:CONFIRMED
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