From Analysis:
RNA binding protein dysregulation across ALS FTD AD
RNA binding protein dysregulation across ALS FTD AD
These hypotheses emerged from the same multi-agent debate that produced this hypothesis.
TDP-43 loss-of-function causes inclusion of a poison exon in STMN2 mRNA, leading to motor neuropathy and contributing to hippocampal axonal dysfunction. Splice-switching oligonucleotides or small molecules that sterically block the poison exon splice site restore STMN2 expression, prevent axonal degeneration, and preserve synaptic connectivity.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with loss of nuclear transactive response DNA-binding protein 43 (TDP-43). Here we identify that TDP-43 regulates expression of the neuronal growth-associated factor stathmin-2. Lowered TDP-43 levels, which reduce i
Transactive response DNA-binding protein 43 kDa (TDP-43), a multifunctional nucleic acid-binding protein, is a primary component of insoluble aggregates associated with several devastating nervous system disorders; mutations in TARDBP, its encoding gene, are a cause of familial amyotrophic lateral s
Loss of nuclear TDP-43 is a hallmark of neurodegeneration in TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 mislocalization results in cryptic splicing and polyadenylation of pre-messenger RNAs (pre-mRNAs) encoding stathmin-2 (also kno
Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal sy
Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence-associated secretory phenotype (SASP) is a potential therapeutic target. Here, w
Description: RBFOX1 (Fox-1), a neuronal splicing regulator, is downregulated when TDP-43 is lost-of-function, leading to aberrant splicing of channels controlling neuronal excitability (e.g., Nav1.1, Cav1.2). Restoring RBFOX1 expression or delivering engineered RBFOX1-responsive antisense oligonucleotides (ASOs) could correct GABAergic dysfunction and hyperexcitability that appears in
1. Limited human tissue validation: The citation provided (29438978) establishes TDP-43 regulates RBFOX1 splicing in cellular models but does not demonstrate RBFOX1 protein reduction in AD patient tissue. The "computational: synaptic_proteomes_db" annotation is a database reference, not a peer-reviewed finding, representing circular reasoning—using synaptic proteomic databases to confirm hypotheses derived from synapt
These hypotheses cluster around an emerging but challenging therapeutic space: RNA binding protein (RBP) dysregulation in neurodegeneration. The field faces three fundamental constraints that must be addressed before any hypothesis graduates from "mechanistically interesting" to "drug development candidate."
Current State of CNS ASO Delivery:
| Event | Price | Change | Source | Time | |
|---|---|---|---|---|---|
| 📄 | New Evidence | $0.675 | ▼ 6.9% | evidence_update | 2026-04-13 10:48 |
| 📄 | New Evidence | $0.725 | ▲ 9.8% | evidence_update | 2026-04-13 10:48 |
| ✨ | Listed | $0.660 | post_process | 2026-04-13 10:48 |
neurodegeneration | 2026-04-13 | failed