DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for juvenile-onset Parkinson disease — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleJuvenile-onset Parkinson disease maps to a 2-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 juvenile-onset parkinson disease 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
Parkinsonism associated deglycase (PARK7) — PARK7 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 9YFR · 0.92 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Mutations in the parkin gene are a major cause of early-onset autosomal recessive familial Parkinson disease and isolated juvenile-onset Parkinson disease, defined as onset at or before age 20. In a 2000 study of 73 families with early-onset disease and 100 isolated patients, 49 percent of families had parkin mutations. Among isolated patients, mutations were found in 10 of 13 patients (77 percent) with onset at 20 or younger, but in only 2 of 64 patients (3 percent) with onset after age 30. Mean age at onset in mutation carriers was 32 years versus 42 years in those without mutations. Patients with parkin mutations were more likely to have symmetric onset, dystonia at onset, hyperreflexia, good response to levodopa, and levodopa-induced dyskinesias. Nineteen different exon rearrangements and 16 different point mutations were detected.
A 1999 European study of 35 families with early-onset autosomal recessive parkinsonism found a wide variety of parkin mutations, including eight previously undescribed point mutations in eight families containing 20 patients. Mean age at onset was 38 years, but onset up to age 58 was observed. The authors concluded that parkin mutations are not invariably associated with early onset, and that in many patients the phenotype is indistinguishable from idiopathic Parkinson disease. A 2003 review noted that, aside from parkin mutations and dopa-responsive dystonia, most causes of juvenile parkinsonism involve additional neurological signs from lesions outside the basal ganglia, and that Lewy body pathology has been reported in only one case, suggesting a juvenile form of idiopathic Parkinson disease may be extremely rare.
A 2002 study evaluating the reliability of reported age at onset in Parkinson disease found excellent agreement among medical records, family history questionnaires, and subject history questionnaires, with an estimated reliability of 0.94 in 149 subjects. A 2017 Russian-language review summarised that Parkinson disease is multifactorial, with genetic predisposition playing a role in both familial and sporadic cases, and that next-generation sequencing continues to identify new gene mutations underlying sporadic cases. A 2014 brief review noted that several gene mutations have shed light on pathogenesis, listing synuclein, parkin, and other genes, but provided no new data on juvenile-onset disease.
What is still missing is a treatment that modifies the course of juvenile-onset Parkinson disease. No drug has been tested in a controlled trial specifically for this population. The existing evidence is limited to genetic characterisation and natural history. A trial would need to stratify patients by genotype, particularly parkin mutation status, and would require long-term follow-up to measure progression. Funding for such a trial remains absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 2000 · 1427 citations · open access
Association between Early-Onset Parkinson's Disease and Mutations in the<i>Parkin</i>Gene
AbstractBACKGROUND: Mutations in the parkin gene have recently been identified in patients with early-onset Parkinson's disease, but the frequency of the mutations and the associated phenotype have not been assessed in a large series of patients. METHODS: We studied 73 families in which at least one of the affected family members was affected at or before the age of 45 years and had parents who were not affected, as well as 100 patients with isolated Parkinson's disease that began at or before the age of 45 years. All subjects were screened for mutations in the parkin gene with use of a semiquantitative polymerase-chain-reaction assay that simultaneously amplified several exons. We sequenced the coding exons in a subgroup of patients. We also compared the clinical features of patients with parkin mutations and those without mutations. RESULTS: Among the families with early-onset Parkinson's disease, 36 (49 percent) had parkin mutations. The age at onset ranged from 7 to 58 years. Among the patients with isolated Parkinson's disease, mutations were detected in 10 of 13 patients (77 percent) with an age at onset of 20 years or younger, but in only 2 of 64 patients (3 percent) with an age at onset of more than 30 years. The mean (+/-SD) age at onset in the patients with parkin mutations was younger than that in those without mutations (32+/-11 vs. 42+/-11 years, P<0.001), and they were more likely to have symmetric involvement and dystonia at onset, to have hyperreflexia at onset or later, to have a good response to levodopa therapy, and to have levodopa-induced dyskinesias during treatment. Nineteen different rearrangements of exons (deletions and multiplications) and 16 different point mutations were detected. CONCLUSIONS: Mutations in the parkin gene are a major cause of early-onset autosomal recessive familial Parkinson's disease and isolated juvenile-onset Parkinson's disease (at or before the age of 20 years). Accurate diagnosis of these cases cannot be based only on the clinical manifestations of the disease.
A Wide Variety of Mutations in the Parkin Gene Are Responsible for Autosomal Recessive Parkinsonism in Europe
AbstractAutosomal recessive juvenile parkinsonism (AR-JP, PARK2; OMIM 602544), one of the monogenic forms of Parkinson's disease (PD), was initially described in Japan. It is characterized by early onset (before age 40), marked response to levodopa treatment and levodopa-induced dyskinesias. The gene responsible for AR-JP was recently identified and designated parkin. We have analysed the 12 coding exons of the parkin gene in 35 mostly European families with early onset autosomal recessive parkinsonism. In one family, a homozygous deletion of exon 4 could be demonstrated. By direct sequencing of the exons in the index patients of the remaining 34 families, eight previously undescribed point mutations (homozygous or heterozygous) were detected in eight families that included 20 patients. The mutations segregated with the disease in the families and were not detected on 110-166 control chromosomes. Four mutations caused truncation of the parkin protein. Three were frameshifts (202-203delAG, 255delA and 321-322insGT) and one a nonsense mutation (Trp453Stop). The other four were missense mutations (Lys161Asn, Arg256Cys, Arg275Trp and Thr415Asn) that probably affect amino acids that are important for the function of the parkin protein, since they result in the same phenotype as truncating mutations or homozygous exon deletions. Mean age at onset was 38 +/- 12 years, but onset up to age 58 was observed. Mutations in the parkin gene are therefore not invariably associated with early onset parkinsonism. In many patients, the phenotype is indistinguishable from that of idiopathic PD. This study has shown that a wide variety of different mutations in the parkin gene are a common cause of autosomal recessive parkinsonism in Europe and that different types of point mutations seem to be more frequently responsible for the disease phenotype than are deletions.
Diagnostic considerations in juvenile parkinsonism
AbstractJuvenile parkinsonism (JP) describes patients in whom the clinical features of parkinsonism manifest before 21 years of age. Many reported cases that had a good response to levodopa have proved to have autosomal recessive juvenile parkinsonism (AR-JP) due to mutations in the parkin gene. With the exception of parkin mutations and dopa-responsive dystonia, most causes are associated with the presence of additional neurological signs, resulting from additional lesions outside of the basal ganglia. Lewy body pathology has only been reported in one case, suggesting that a juvenile form of idiopathic Parkinson's disease may be extremely rare.
Reliability of reported age at onset for Parkinson's disease
AbstractAn individual's age at onset of Parkinson disease (PD) can be collected through a variety of sources, including medical records, family report, and clinical observation. The most common source of PD age at onset information in the research setting is family-report, which is then typically used to classify a subject as juvenile, young, or late age at onset. The reliability of the family-reported age at onset of PD has not been rigorously examined. The present study used data from individuals diagnosed with PD to evaluate the reliability of age at onset information by comparing data obtained from three sources: 1) the subject's medical records, 2) a Family History Questionnaire, and 3) a Subject History Questionnaire. Among the 149 subjects with data for all three age at onset sources, the estimated reliability was R = 0.94. Similar reliability was observed when the sample was stratified based on gender, age at examination, disease duration, first symptom of PD, and years of education. The three measures of age at onset of PD show excellent agreement, strengthening confidence in the reliability of the reported age of clinical onset for PD.
DOAJ (DOAJ: Directory of Open Access Journals) · 2017 · 2 citations
Генетическая основа болезни Паркинсона
AbstractParkinson's disease (PD) is a multifactorial disease that develops in the presence of both genetic and environmental factors. In recent years, there has been sufficient information on the role of genetic predisposition in the development of not only familial cases, but also sporadic ones. A hereditary burden in PD may not be traced in cases of recessive inheritance with a low gene penetrance, as well as in a patient's death before the onset of the disease. Active introduction of molecular genetic methods, including next generation sequencing, can annually identify new gene mutations that underlie sporadic PD cases. This paper provides an overview of the current literature on the genetic aspects of PD with emphasis on the ethnic characteristics of the disease.
Journal of Evolution of Medical and Dental Sciences · 2014 · 1 citations · open access
PARKINSON’S DISEASE: A BRIEF REVIEW
AbstractParkinson's disease (PD) is an age-related neurodegenerative disorder affecting many people in the world. Several gene mutations have shed light on the mechanisms of pathogenesis of PD. The parkinsonian syndrome is associated with several other degenerative and non-degenerative diseases. Genes linked to PD are synuclein, Parkinson's disease autosomal recessive, juvenile 2, Parkinson's disease autosomal recessive, early onset 7, PTEN-induced putative kinase 1 and leucinerich repeat kinase 2. The initial symptomatic therapy and adjuvant therapy in later PD are also discussed.
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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