TDP-43 Suppression of Non-conserved Cryptic Exons is Compromised in Human Neurodegenerative Diseases

Case ID:
C13621

C13621: Suppression of Non-conserved Cryptic Exons is Compromised in Human Neurodegenerative Diseases

 

 

Abstract

 

A novel mechanism underlying the suppression of non conserved cryptic exons. This mechanism is essential to maintain intron integrity, and is compromised in ALS-FTD, indicating that loss of function underlies pathogenesis of disease. Publication abstract: Cytoplasmic aggregation of TDP-43, accompanied by its nuclear clearance, is a key common pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, a limited understanding of this RNA-binding protein (RBP) impedes the clarification of pathogenic mechanisms underlying TDP-43 proteinopathy. In contrast to RBPs that regulate splicing of conserved exons, we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity. When TDP-43 was depleted from mouse embryonic stem cells, these cryptic exons were spliced into messenger RNAs, often disrupting their translation and promoting nonsense-mediated decay. Moreover, enforced repression of cryptic exons prevented cell death in TDP-43-deficient cells. Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy.

US Patent application filed claiming priority to PCT application published as WO 2016/205615.

Patent Information:
Title App Type Country Serial No. Patent No. File Date Issued Date Expire Date Patent Status
TDP-43 Suppression of Non-conserved Cryptic Exons is Compromised in Human Neurodegenerative Diseases PCT: Patent Cooperation Treaty PCT PCT/US2016/038037   6/17/2016     Expired
TDP-43 Suppression of Non-conserved Cryptic Exons is Compromised in Human Neurodegenerative Diseases PCT: Patent Cooperation Treaty United States 15/737,489 10,962,551 12/18/2017 3/30/2021 6/17/2036 Granted
TDP-43 IN DEGENERATIVE DISEASE CON: Continuation United States 17/189,967   3/2/2021     Pending
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For Information, Contact:
Michael Woods
mwoods19@jh.edu
410-614-0300
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