A missense mutation in the PLA2G6 gene (chr22:g.38112558C > T) resulting in p.Arg741Gln substitution is implicated in young-onset Parkinson disease (YOPD), which presents with early motor symptoms clinically indistinguishable from other PD etiologies. Induced pluripotent stem cells (iPSCs) were generated from peripheral blood mononuclear cells of a PLA2G6 p.Arg741Gln patient with UPDRS-confirmed PD diagnosis using Sendai virus reprogramming technology. Complete characterization validated self-renewal capacity and pluripotency markers. This patient-derived iPSC line represents a valuable cellular model for mechanistic studies and drug discovery efforts targeting PLA2G6-associated Parkinsonism.

The PTEN-induced kinase 1 (PINK1) gene mutation is the second most prevalent young-onset Parkinson disease (YOPD) characterized by early onset of motor symptoms that are often indistinguishable from other causes of PD. Induced pluripotent stem cells (iPSCs) were derived from peripheral blood mononuclear cells of a PD patient with PINK1 variant c.1208G > A, p.Trp403Ter using Sendai-virus reprogramming. PD diagnosis was confirmed via the Unified Parkinson's Disease Rating Scale (UPDRS). Characterization of the iPSC line ensured self-renewal and pluripotency. This resource serves as a valuable platform for drug screening and elucidating the pathophysiology of this mutation, facilitating advancements in PD research. PINK1 type of young-onset Parkinson disease is characterized by early onset (median age at onset 32 years) of tremor, bradykinesia, and rigidity that are often indistinguishable from other causes of Parkinson disease. Lower-limb dystonia may be a presenting sign. Postural instability, hyperreflexia, abnormal behavior, and psychiatric manifestations have been described. The disease is usually slowly progressive. Individuals have a marked and sustained response to oral administration of levodopa (L-dopa), frequently associated with L-dopa-induced fluctuations and dyskinesias. The diagnosis of PINK1 type of young-onset Parkinson disease is established by the identification of biallelic PINK1 pathogenic variants on molecular genetic testing. Treatment of manifestations: PINK1 type of young-onset Parkinson disease usually responds well to L-dopa and/or other dopamine agonists, which may be used in combination with catechol-O-methyltransferase inhibitors or monoamine oxidase-B inhibitors, anticholinergics, and amantadine. Physical therapy and/or occupational therapy to improve and/or maintain gross motor and fine motor skills as well as speech therapy. Invasive therapies include intrajejunal L-dopa-carbidopa pump, subcutaneous apomorphine pump, or deep brain stimulation. L-dopa-induced dyskinesias can be treated by reducing L-dopa dose, switching to dopamine receptor agonists, deep brain stimulation, or continuous treatment with L-dopa or apomorphine. Atypical neuroleptic agents can be used for neuropsychiatric manifestations; standard treatments for depression. Cholinesterase inhibitors can be used to treat dementia. Consider droxidopa, midodrine, fludrocortisone, and/or supportive measures for orthostasis. Symptomatic treatment for constipation. Surveillance: Neurologic evaluation every three to 12 months to assess motor and non-motor manifestations and treatment efficacy; in addition, assess for atypical manifestations and therapy needs at each visit. Neuropsychiatric evaluation in those with mood disorder / psychotic symptoms or as needed. Cognitive assessment annually or as needed. At each visit, assess nutrition and safety of feeding; assess for symptoms of orthostasis and measure supine and standing blood pressure and pulse; assess for constipation, urinary urgency, or urge incontinence; and assess family needs. Agents/circumstances to avoid: Neuroleptic treatment may exacerbate parkinsonism. PINK1 type of young-onset Parkinson disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PINK1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial PINK1 pathogenic variants. Once the PINK1 pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Young onset Parkinson disease (YOPD) accounts for about 10% of PD patients, with the onset of symptoms between the ages of 21 and 40. At this age, the probability of pregnancy is high and there is a concern that the disease affects the fetuses. Therefore, in the present study, the effects of rotenone-induced PD on female mice as well as their fetuses and curcumin supplementation on the cerebral tissue of both female mice and their resulted fetuses were studied. The rotenone was injected subcutaneously to induce PD model of female mice. The different concentrations of curcumin were administrated every day i.p. for 3 weeks and the rotarod test was done on day 1 and 19. Cell viability was measured by MTT test and apoptosis and necrosis of cells were evaluate using flow cytometry technique. After primer design, the expressions of bax, bcl-2, miR-211 and circRNA 0001518 genes were measured using RT-PCR technique. Curcumin administration were improved cerebral cell viability of both female PD mice and resulted fetuses by preventing cell apoptosis and necrosis. bax, miR-211 and circRNA 0001518 were downregulated and bcl-2 overexpressed in cerebral neurons of PD mice and their fetuses. PD induction in mice affects their fetal brain, and curcumin can partially reduce the negative effects of PD on fetal brain cells by overexpressing bcl-2 and decreasing bax expression genes.

Parkinson disease (PD) is a common age-related neurodegenerative disease. Subthalamic nucleus deep brain stimulation (DBS) is a safe and effective surgical treatment for medically resistant advanced PD. However, the relationship between the age at PD onset and the efficacy of subthalamic nucleus DBS surgery remains unclear. Thus, we conducted a meta-analysis to compare motor symptom improvements after DBS for the treatment of young-onset and late-onset PD. We systematically searched the Medline and Embase databases (from inception to March 2023) for English publications. All published studies comparing the outcomes (Unified Parkinson's Disease Rating Scale part III [UPDRS III] scores) of DBS between the young-onset Parkinson disease (YOPD) and late-onset Parkinson disease (LOPD) groups were identified. The effect size was defined as the standardized mean difference (Hedge g) with 95% confidence intervals. The standardized mean difference was calculated by dividing the difference in UPDRS III scores between old and young patients by the pooled and weighted standard deviations. The meta-analysis was performed using R Statistical Software version 4.2.2 (The R Foundation for Statistical Computing). Six studies were eligible for inclusion. The standardized mean difference of UPDRS III score between young and old patients ranged from -0.54 to 1.43 with a pooled difference of 0.0932 (95% confidence intervals: - 0.4666 to 0.6530, I2 = 86.77%). Subgroup analyses were performed with a cutoff age of 65 years and did not show a significant difference in UPDRS III scores between patients with YOPD and LOPD (0.1877, -0.6663 to 1.0417). The efficacy of DBS in patients with YOPD and LOPD showed similar improvements in the UPDRS score; hence, DBS should be considered, if necessary, regardless of the onset age of PD.

We recently discovered that the expression of PRKN, a young-onset Parkinson disease-linked gene, confers redox homeostasis. To further examine the protective effects of parkin in an oxidative stress model, we first combined the loss of prkn with Sod2 haploinsufficiency in mice. Although adult prkn-/-//Sod2± animals did not develop dopamine cell loss in the S. nigra, they had more reactive oxidative species and a higher concentration of carbonylated proteins in the brain; bi-genic mice also showed a trend for more nitrotyrosinated proteins. Because these redox changes were seen in the cytosol rather than mitochondria, we next explored the thiol network in the context of PRKN expression. We detected a parkin deficiency-associated increase in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) in murine brain, PRKN-linked human cortex and several cell models. This shift resulted from enhanced recycling of GSSG back to GSH via upregulated glutathione reductase activity; it also correlated with altered activities of redox-sensitive enzymes in mitochondria isolated from mouse brain (e.g., aconitase-2; creatine kinase). Intriguingly, human parkin itself showed glutathione-recycling activity in vitro and in cells: For each GSSG dipeptide encountered, parkin regenerated one GSH molecule and was S-glutathionylated by the other (GSSG + P-SH [Formula: see text] GSH + P-S-SG), including at cysteines 59, 95 and 377. Moreover, parkin's S-glutathionylation was reversible by glutaredoxin activity. In summary, we found that PRKN gene expression contributes to the network of available thiols in the cell, including by parkin's participation in glutathione recycling, which involves a reversible, posttranslational modification at select cysteines. Further, parkin's impact on redox homeostasis in the cytosol can affect enzyme activities elsewhere, such as in mitochondria. We posit that antioxidant functions of parkin may explain many of its previously described, protective effects in vertebrates and invertebrates that are unrelated to E3 ligase activity.