DeCure for GRN-related frontotemporal lobar degeneration with Tdp43 inclusions
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for GRN-related frontotemporal lobar degeneration with Tdp43 inclusions — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleGRN-related frontotemporal lobar degeneration with Tdp43 inclusions maps to a 3-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for grn-related frontotemporal lobar degeneration with tdp43 inclusions is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
transmembrane protein 106B (TMEM106B) — TMEM106B is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8OTD · 2.6 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
GRN mutations account for about 5–10% of frontotemporal lobar degeneration (FTLD) cases, and in one cohort of 225 patients, 8.4% carried a GRN mutation, similar to the 8.9% with MAPT mutations. No mutations were found in VCP, CHMP2B, TARDBP, or FUS in that same cohort. Among patients with a strong family history but no known mutation, six had type 3 FTLD-TDP pathology without GRN mutations, indicating other undiscovered genes. Heritability varies by clinical subtype: the behavioural variant is most heritable, while frontotemporal dementia–motor neuron disease and semantic dementia are least heritable. Only 10.2% of patients had a clear autosomal dominant family history, though 41.8% had some family history.
Loss-of-function GRN mutations cause haploinsufficiency of progranulin, which is a major genetic risk factor for FTLD with TDP-43 inclusions. A cellular mechanism represses translation of GRN mRNAs that carry a long 5′ untranslated region (219 nucleotides) containing an upstream open reading frame (uORF). This uORF, specifically a short stretch between nucleotides 76 and 125 with two start codons, is required and sufficient to repress protein expression. Mutagenesis of those two AUG codons reduces translational repression. The long 5′ UTR also reduces mRNA stability, so two independent mechanisms—mRNA stability and translational efficiency—control GRN expression.
Novel GRN mutations continue to be identified. In 45 unrelated Canadian patients with FTLD-like syndromes (mean onset age 64.0 years), two carried novel heterozygous alterations: a 2 bp insertion (c.769-770insCC, p.Q257fs) and a 12 bp deletion (c.1009-1020del, p.337-340del). Both presented with corticobasal syndrome. The 2 bp insertion showed absence of the mutant allele in RT-PCR product, consistent with nonsense-mediated decay; the 12 bp deletion was not down-regulated at RNA level and did not segregate with FTLD in the family. Another report described a novel GRN c.708+6_+9delTGAG mutation in six cases from four families, all with TDP-43–positive inclusions. A further novel mutation, c.687T>A, p.(Tyr229*), caused haploinsufficiency and a severe neuropathological FTLD phenotype with TDP-43 inclusions in a proband presenting at age 60 with dyspraxia, dysgraphia, and dysphasia; a nephew had similar but milder pathology.
What is still missing is a clear understanding of the remaining genetic causes in familial FTLD-TDP without GRN mutations, and a therapeutic strategy that can reliably increase progranulin levels in the brain. No clinical trial has yet shown that raising progranulin slows or halts disease progression in GRN mutation carriers. The heterogeneity of clinical presentation and the incomplete penetrance of some mutations complicate trial design and patient stratification. Funding for large, longitudinal natural history studies and for therapies that target the translational repression mechanism described in 2014 remains insufficient.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neurology · 2009 · 539 citations · open access
The heritability and genetics of frontotemporal lobar degeneration
AbstractBACKGROUND: Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder. METHODS: We collected blood samples from a cohort of 225 patients with a diagnosis within the FTLD spectrum and examined the heritability of FTLD by giving each patient a family history score, from 1 (a clear autosomal dominant history of FTLD) through to 4 (no family history of dementia). We also looked for mutations in each of the 5 disease-causing genes (MAPT, GRN, VCP, CHMP2B, and TARDP) and the FUS gene, known to cause motor neuron disease. RESULTS: A total of 41.8% of patients had some family history (score of 1, 2, 3, or 3.5), although only 10.2% had a clear autosomal dominant history (score of 1). Heritability varied across the different clinical subtypes of FTLD with the behavioral variant being the most heritable and frontotemporal dementia-motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable. Mutations were found in MAPT (8.9% of the cohort) and GRN (8.4%) but not in any of the other genes. Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without GRN mutations (6) and FTLD-UPS (1). CONCLUSION: These findings show that frontotemporal lobar degeneration (FTLD) is a highly heritable disorder but heritability varies between the different syndromes. Furthermore, while MAPT and GRN mutations account for a substantial proportion of familial cases, there are other genes yet to be discovered, particularly in patients with type 3 FTLD-TDP without a GRN mutation.
Journal of Biological Chemistry · 2014 · 38 citations · open access
Progranulin Transcripts with Short and Long 5′ Untranslated Regions (UTRs) Are Differentially Expressed via Posttranscriptional and Translational Repression
AbstractFrontotemporal lobar degeneration is associated with cytoplasmic or nuclear deposition of the TAR DNA-binding protein 43 (TDP-43). Haploinsufficiency of progranulin (GRN) is a major genetic risk factor for frontotemporal lobar degeneration associated with TDP-43 deposition. Therefore, understanding the mechanisms that control cellular expression of GRN is required not only to understand disease etiology but also for the development of potential therapeutic strategies. We identified different GRN transcripts with short (38-93 nucleotides) or long (219 nucleotides) 5' UTRs and demonstrate a cellular mechanism that represses translation of GRN mRNAs with long 5' UTRs. The long 5' UTR of GRN mRNA contains an upstream open reading frame (uORF) that is absent in all shorter transcripts. Because such UTRs can be involved in translational control as well as in mRNA stability, we compared the expression of GRN in cells expressing cDNAs with and without 5' UTRs. This revealed a selective repression of GRN translation and a reduction of mRNA levels by the 219-nucleotide-long 5' UTR. The specific ability of this GRN 5' UTR to repress protein expression was further confirmed by its transfer to an independent reporter. Deletion analysis identified a short stretch between nucleotides 76 and 125 containing two start codons within one uORF that is required and sufficient for repression of protein expression. Mutagenesis of the two AUG codons within the uORF is sufficient to reduce translational repression. Therefore initiating ribosomes at the AUGs of the uORF fail to efficiently initiate translation at the start codon of GRN. In parallel the 5' UTR also affects mRNA stability; thus two independent mechanisms determine GRN expression via mRNA stability and translational efficiency.
Scientific Reports · 2016 · 11 citations · open access
Novel GRN Mutations in Patients with Corticobasal Syndrome
AbstractLoss-of-function GRN mutations lead to GRN haploinsufficiency and consequently neurodegeneration with significant heterogeneity in clinical presentation of various syndromes. The aim of this study was to investigate the genetics and clinical features of patients with GRN-related frontotemporal lobar degeneration (FTLD) syndromes. We performed mutation analysis of GRN in 45 unrelated Canadian patients with a broad spectrum of FTLD-like syndromes (mean age at onset of 64.0 ± 11.2 years). In our cohort, two patients were carriers of two novel heterozygous alterations in GRN: 2 bp insertion (c.769-770insCC:p.Q257fs) and 12 bp deletion (c.1009-1020del:p.337-340del). Both patients presented with corticobasal syndrome supported by clinical and radiological findings. The absence of the mutant allele in the RT-PCR product was only observed for the sample with 2 bp insertion in GRN. In contrast, the allele with 12 bp deletion in GRN was not down-regulated at the RNA level and did not segregate with FTLD in the family. Our report extends the evidence for genetic and phenotypic variability in FTLD disorders, and detects a novel pathogenic GRN mutation, carriers of which could eventually help to evaluate the efficacy of different treatments at early stages of dementia.
Journal of Neuropathology & Experimental Neurology · 2014 · 9 citations · open access
A Novel<i>GRN</i>Mutation (<i>GRN</i>c.708+6_+9delTGAG) in Frontotemporal Lobar Degeneration With TDP-43–Positive Inclusions
AbstractUnderstanding of frontotemporal lobar degeneration, the underlying pathology most often linked to the clinical diagnosis of frontotemporal dementia, is rapidly increasing. Mutations in 7 known genes (MAPT, GRN, C9orf72, VCP, CHMP2B, and, rarely, TARDBP and FUS) are associated with frontotemporal dementia, and the pathologic classification of frontotemporal lobar degeneration has recently been modified to reflect these discoveries. Mutations in one of these genes (GRN), which encodes progranulin, have been implicated in up to a quarter of cases of frontotemporal lobar degeneration with TDP-43 (TAR DNA-binding protein 43)-positive inclusions; currently, there are more than 60 known pathogenic mutations of the gene. We present the clinical, pathologic, and genetic findings on 6 cases from 4 families, 5 of which were shown to have a novel GRN c.708+6_+9delTGAG mutation.
Journal of Alzheimer s Disease · 2016 · 6 citations
Genetics of Frontotemporal Lobar Degeneration: From the Bench to the Clinic
AbstractFrontotemporal lobar degeneration (FTLD) is a clinically heterogeneous neurodegenerative disease with a strong genetic component. In this review, we summarize most common mutations in MAPT, GRN, and C90RF72, as well as less common mutations in VCP, CHMP2B, TARDBP, FUS gene and so on. Several guidelines have been developed to help gene testing based on genotype-phenotype correlation, the underlying histopathological subtypes, and the neuroanatomic associations. Furthermore, we also summarize molecular pathways implicated by genes and novel targets for FTLD prevention and management in recent years.
Journal of Alzheimer s Disease · 2016 · 6 citations · open access
A Novel Loss-of-Function GRN Mutation p.(Tyr229*): Clinical and Neuropathological Features
AbstractMutations in the progranulin (GRN) gene represent about 5-10% of frontotemporal lobar degeneration (FTLD). We describe a proband with a novel GRN mutation c.687T>A, p.(Tyr229*), presenting with dyspraxia, dysgraphia, and dysphasia at the age of 60 and a very severe FTLD neuropathological phenotype with TDP43 inclusions. The nephew of the proband had signs of dementia and personality changes at the age of 60 and showed similar but milder FTLD pathology. Three other family members had had early-onset dementia. Gene expression studies showed decreased GRN gene expression in mutation carriers' blood samples. In conclusion, we describe a novel GRN, p.(Tyr229*) mutation, resulting in haploinsufficiency of GRN and a severe neuropathologic FTLD phenotype.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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