DeCure for Parkinson disease 22, autosomal dominant
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for Parkinson disease 22, autosomal dominant — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleParkinson disease 22, autosomal dominant maps to a 1-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 parkinson disease 22, autosomal dominant 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.
What the evidence adds up to
The G2019S mutation in LRRK2 was identified as a cause of autosomal dominant Parkinson's disease in 2005. In a study of 198 probands with autosomal dominant PD, the frequency in North African families was 41% (7/17), compared to 2.9% (5/174) in European families. Among 21 patients, including one with a homozygous mutation, clinical features were those of typical PD, with lower Mini-Mental State Examination scores. There were also 15 unaffected mutation carriers aged 32 to 74 years.
A 2020 multi-centre cohort of 1805 index cases (592 with autosomal dominant inheritance, 1213 isolated cases) found pathogenic variants in 160 index cases (8.9%): 138 with pathogenic LRRK2 variants (7.6%), 136 of which were Gly2019Ser; 19 with SNCA mutations (1.1%); and three with VPS35 Asp620Asn (0.16%). Mutation frequencies were higher in familial than isolated cases (12.0% vs. 7.3%; OR 1.7, 95% CI 1.2-2.4, p = 0.003). LRRK2 carriers were more likely to have late-onset PD (>50 years; OR 1.5, 95% CI 1.0-2.2, p = 0.03), while SNCA mutation carriers tended toward earlier onset (≤50 years, p = 0.06). Clinical features of LRRK2 carriers and non-carriers were similar.
A 1977 study of 12 families found that affected second-degree relatives were bilaterally distributed more often than expected for autosomal dominance, suggesting a multifactorial aetiology for most PD cases, though dominant gene inheritance in some families was not ruled out. A 2006 clinic-based screening of 311 subjects (202 cases, 109 controls) for three LRRK2 mutations found only one sporadic case with a heterozygous G2019S mutation. In a 2013 study of 240 young-onset PD patients (mean onset 43.6 years), 12.5% had a first-degree relative with PD, 13.3% had a second-degree relative, and 23.7% had any family member affected. Parental history was present in 10.8%, and about one tenth of patients were estimated to have autosomal dominant inheritance.
What remains missing is systematic genetic testing in large, diverse populations to establish penetrance and age-related risk for LRRK2 carriers, particularly in North African cohorts where the mutation is common. No trial has tested whether targeting LRRK2 alters disease progression. The clinical similarity between LRRK2 carriers and non-carriers means that patient stratification for any future study would require genotyping, not phenotype alone. Funding for such a trial, and for long-term follow-up of unaffected carriers, is 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.
Annals of Neurology · 2005 · 212 citations · open access
G2019S LRRK2 mutation in French and North African families with Parkinson's disease
AbstractMutations in LRRK2 were recently identified in autosomal dominant Parkinson's disease (PD), including the G2019S mutation. To evaluate its frequency, we analyzed 198 probands with autosomal dominant PD, mostly from France and North Africa. Surprisingly, the frequency in North African families (7/17, 41%) was greater than those from Europe (5/174, 2.9%). The clinical features in 21 patients, including 1 with a homozygous mutation, were those of typical PD, with lower Mini-Mental State Examination scores. There were also 15 unaffected mutation carriers, aged 32 to 74 years. LRRK2 mutations appear to be a common cause of autosomal dominant PD, particularly in North Africa.
Frontiers in Neurology · 2020 · 47 citations · open access
Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort
AbstractLRRK2, SNCA and VPS35 are unequivocally associated with autosomal dominant Parkinson’s disease (PD). We evaluated the prevalence of LRRK2, SNCA and VPS35 mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1805 index cases (592 with autosomal dominant inheritance and 1213 isolated cases) since 1990. All probands were screened with TaqMan assays for LRRK2 Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic LRRK2 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with SNCA point mutations or genomic rearrangements (1.1%), and three with the VPS35 Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0% vs. 7.3%; OR 1.7, 95% CI [1.2-2.4], p = 0.003). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (> 50 years; OR 1.5, 95% CI [1.0-2.2], p = 0.03), whereas those with SNCA mutations tended to have earlier age at onset disease (≤ 50 years, p = 0.06). The clinical features of LRRK2 carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.
The distribution of ancestral secondary cases in Parkinson's disease
AbstractRecent evidence suggests a genetic mode of transmission of Parkinson's disease. A multifactorial mechanism is likely, but autosomal dominance with reduced penetrance has not been excluded. The distribution of ancestral second-degree relatives with Parkinson's disease was evaluated in 12 families. Affected relatives were bilaterally distributed more often than would be expected for autosomal dominance. The distribution of ancestral secondary cases suggests a multifactorial etiology for most cases of Parkinson's disease. The possibility of dominant gene inheritance in some families is not entirely ruled out.
European Journal of Neurology · 2006 · 6 citations
<i>LRRK2</i> mutations in a clinic‐based cohort of Parkinson's disease
AbstractIn the last decade, major breakthroughs in the understanding of genetic contributions to Parkinson's disease (PD) have been achieved. Recently, mutations in LRRK2, encoding dardarin, have been found to be responsible for an autosomal dominant parkinsonism (OMIM 607060). We screened 311 subjects (cases: n = 202, controls: n = 109) for the three previously reported LRRK2 mutations. Our investigation revealed a sporadic case of PD with a heterozygous mutation G2019S (c.6055G>A). Here, we present the clinical phenotype of this patient and discuss the implications of genetic testing for the G2019S mutation in patients with sporadic PD.
Abstract<h3>Background</h3> Young onset Parkinson9s disease is more likely to be genetic than older onset Parkinson9s disease, particularly with a positive family history, and there are also racial differences.<sup>1 2</sup> Both autosomal dominant and recessive causes of Parkinson9s disease are described; analysis of family history data is instructive regarding genetic risk and likely inheritance patterns. <h3>Methods</h3> Detailed family histories were obtained from young onset (<50 years old) Parkinson9s disease patients by the Parkinson9s Repository of Biosamples and Networked Datasets (PRoBaND) clinical consortium. <h3>Results</h3> In 240 cases enrolled, the mean age of onset of Parkinson9s disease was 43.6 years (SD 5.8), mean disease duration was 10.2 years (SD 6.8) and 69.3% are male. Most (94.1%) were Caucasian; the largest ethnicity was white British (89.1%); 3.2% were of Asian, and 0.5% of African heritage. There was a family history of Parkinson9s disease in one or more first degree relative in 12.5%, one or more second degree relative in 13.3%, and one or more family members had Parkinson9s disease in 23.7% of the index cases (Figure). The positive first degree family history was parental in 10.8% of patients, in one or more siblings in 2.5% of cases, and one or more children in <0.5% of cases. 5.8% had a maternal grandparent, and 2.9% had a paternal grandparent with PD. <h3>Conclusion</h3> Positive family histories in about a quarter of young onset PD patients is similar to previous studies.<sup>3</sup> Around one tenth of patients in this population may have autosomal dominant inheritance. Far fewer have a family history pattern suggesting autosomal recessive inheritance, but this may be underestimated from family tree assessment. Genetic testing is now underway in our cohort, both for known genes including GBA, LRRK2, PARKIN, PINK1, and SNCA, but also for the analysis of genetic variation (single nucleotide polymorphism) that may be of greater significance to the presence and severity of disease–related complications, such as cognitive impairment and therapy responses.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
