Mutations In DJ-1 Research Articles

Nuclear DJ-1 Regulates DNA Damage Repair via the Regulation of PARP1 Activity.

DNA damage and defective DNA repair are extensively linked to neurodegeneration in Parkinson's disease (PD), but the underlying molecular mechanisms remain poorly understood. Here, we determined that the PD-associated protein DJ-1 plays an essential role in modulating DNA double-strand break (DSB) repair. Specifically, DJ-1 is a DNA damage response (DDR) protein that can be recruited to DNA damage sites, where it promotes DSB repair through both homologous recombination and nonhomologous end joining. Mechanistically, DJ-1 interacts directly with PARP1, a nuclear enzyme essential for genomic stability, and stimulates its enzymatic activity during DNA repair. Importantly, cells from PD patients with the DJ-1 mutation also have defective PARP1 activity and impaired repair of DSBs. In summary, our findings uncover a novel function of nuclear DJ-1 in DNA repair and genome stability maintenance, and suggest that defective DNA repair may contribute to the pathogenesis of PD linked to DJ-1 mutations.

Upregulation of DJ-1 in Dopaminergic Neurons by a Physically-Modified Saline: Implications for Parkinson’s Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder in human and loss-of-functions DJ-1 mutations are associated with a familial form of early onset PD. Functionally, DJ-1 (PARK7), a neuroprotective protein, is known to support mitochondria and protect cells from oxidative stress. Mechanisms and agents by which the level of DJ-1 could be increased in the CNS are poorly described. RNS60 is a bioactive aqueous solution created by exposing normal saline to Taylor-Couette-Poiseuille flow under high oxygen pressure. Recently we have described neuroprotective, immunomodulatory and promyelinogenic properties of RNS60. Here we delineate that RNS60 is also capable of increasing the level of DJ-1 in mouse MN9D neuronal cells and primary dopaminergic neurons, highlighting another new neuroprotective effect of RNS60. While investigating the mechanism we found the presence of cAMP response element (CRE) in DJ-1 gene promoter and stimulation of CREB activation in neuronal cells by RNS60. Accordingly, RNS60 treatment increased the recruitment of CREB to the DJ-1 gene promoter in neuronal cells. Interestingly, RNS60 treatment also induced the enrollment of CREB-binding protein (CBP), but not the other histone acetyl transferase p300, to the promoter of DJ-1 gene. Moreover, knockdown of CREB by siRNA led to the inhibition of RNS60-mediated DJ-1 upregulation, indicating an important role of CREB in DJ-1 upregulation by RNS60. Together, these results indicate that RNS60 upregulates DJ-1 in neuronal cells via CREB-CBP pathway. It may be of benefit for PD and other neurodegenerative disorders.

Advancement of biomolecular engineering in Parkinson disease

Parkinson's Condition (PD) is the second most common degenerative neurological disease, affecting 10 million people globally. Nigrostriatal degeneration is linked to decreased motor and non-motor functioning in this chronic illness. Resting tremor, stiffness, akinesia (or bradykinesia), and postural instability are the four cardinal symptoms of Parkinson's disease. Because the symptoms of Parkinson's disease are similar to those of other age-related disorders like SWEDD (scans without evidence of dopaminergic deficit), essential tremors, and Parkinson's disease, early diagnosis is difficult. A synucleinopathy is Parkinson's disease (PD) with Lewy Bodies (DLB).Although both genetic and environmental variables are assumed to play a role in Parkinson's disease (PD), there was no direct evidence to support either as a causal component until recently. Six distinct genes have been discovered as producing familial PD in the last eight years. They back up the idea that similar pathogenetic pathways exist across the spectrum of Parkinson's disease etiologies. Mutations in α-synuclein, parkin, UCHL1, DJ1, PINK1, and LRRK2 cause.Parkinson's disease, which is inherited in a Mendelian form. Overexpression of α- synuclein and parkin causes mitochondrial issues, but DJ1 and PINK1 are mitochondrial proteins. These same proteins regulate proteasomal function and play a role in the oxidative stress response.Doped carbon nanotubes, especially phosphorus-doped carbon nanotubes, can efficiently prevent the formation of α- synuclein amyloid, suggesting that they could be utilized to treat Parkinson's disease. More in vitro and clinical research is, however, necessary. As previously stated, αsynuclein could be a therapeutic target for Parkinson's disease and other synucleinopathies. The most promising option would be small chemicals that may modify the structure of protofibrillar forms of α-synuclein and render them nonpathogenic. Given the pathogenic consequences of αsynuclein's feed-forward amplification loops, a range of therapeutic options will almost certainly be required.

Biomarker of Neuroinflammation in Parkinson's Disease.

Parkinson’s disease (PD) is caused by abnormal accumulation of α-synuclein in dopaminergic neurons of the substantia nigra, which subsequently causes motor symptoms. Neuroinflammation plays a vital role in the pathogenesis of neurodegeneration in PD. This neuroinflammatory neurodegeneration involves the activation of microglia, upregulation of proinflammatory factors, and gut microbiota. In this review, we summarized the recent findings on detection of PD by using inflammatory biomarkers, such as interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor (TNF)-α; regulated upon activation, normal T cell expressed and presumably secreted (RANTES) and high-sensitivity c-reactive protein (hsCRP); and radiotracers such as [11C]PK11195 and [18F]-FEPPA, as well as by monitoring disease progression and the treatment response. Many PD-causing mutations in SNCA, LRRK2, PRKN, PINK1, and DJ-1 are also associated with neuroinflammation. Several anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs (NSAID), inhibitors of TNF-α and NLR family pyrin domain containing 3 (NLRP3), agonists of nuclear factor erythroid 2-related factor 2 (NRF2), peroxisome proliferator-activated receptor gamma (PPAR-γ), and steroids, have demonstrated neuroprotective effects in in vivo or in vitro PD models. Clinical trials applying objective biomarkers are required to investigate the therapeutic potential of anti-inflammatory medications for PD.

Early-Onset Parkinson's Disease and Brain Iron Accumulation Caused by a Novel Homozygous DJ-1 Mutation.

DJ-1 mutations are rare causes of autosomal recessive early-onset Parkinson's disease (AR-EOPD) and relatively rarely reported in the Chinese population. Here, we used the whole-exome sequencing and Sanger sequencing to investigate DJ-1 mutations in the Chinese population and confirmed the pathogenicity of the mutation using primary fibroblasts established from skin biopsies. We identified a novel homozygous mutation (c.390delA, p.D131Tfs*3) in DJ-1 in a consanguineous Chinese family. The proband in this family had parkinsonism at the age of 22. His brain MRI indicated brain iron accumulation in the basal ganglia and cerebellum. The novel mutation caused DJ-1 protein deficiency, led to mitochondrial dysfunction, inhibited cell proliferation, and anti-oxidant defense.

Unfolding is the driving force for mitochondrial import and degradation of the Parkinson's disease-related protein DJ-1

ABSTRACTDiverse genes associated with familial Parkinson's disease (familial Parkinsonism) have been implicated in mitochondrial quality control. One such gene, PARK7 encodes the protein DJ-1, pathogenic mutations of which trigger its translocation from the cytosol to the mitochondrial matrix. The translocation of steady-state cytosolic proteins like DJ-1 to the mitochondrial matrix upon missense mutations is rare, and the underlying mechanism remains to be elucidated. Here, we show that the protein unfolding associated with various DJ-1 mutations drives its import into the mitochondrial matrix. Increasing the structural stability of these DJ-1 mutants restores cytosolic localization. Mechanistically, we show that a reduction in the structural stability of DJ-1 exposes a cryptic N-terminal mitochondrial-targeting signal (MTS), including Leu10, which promotes DJ-1 import into the mitochondrial matrix for subsequent degradation. Our work describes a novel cellular mechanism for targeting a destabilized cytosolic protein to the mitochondria for degradation.

Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson\u2019s disease and dementia with Lewy bodies

The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (α-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded α-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to α-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC α-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive α-Syn seeding in 93% of patients carrying severe GBA mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe GBA mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with GBA mutations showed positive α-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between α-Syn seeding activity and reduced CSF levels of proteins linked to α-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF.These findings highlight the value of α-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn.

α-Synuclein Deposition in Sympathetic Nerve Fibers in Genetic Forms of Parkinson's Disease.

Cytoplasmic inclusions of α-synuclein (α-syn) in brainstem neurons are characteristic of idiopathic Parkinson's disease (PD). PD also entails α-syn buildup in sympathetic nerves. Among genetic forms of PD, the relative extents of sympathetic intraneuronal accumulation of α-syn have not been reported. This cross-sectional observational study compared magnitudes of intraneuronal deposition of α-syn in common and rare genetic forms of PD. α-Syn deposition was quantified by the α-syn-tyrosine hydroxylase colocalization index in C2 cervical skin biopsies from 65 subjects. These included 30 subjects with pathogenic mutations in SNCA (n=3), PRKN [biallelic (n=7) and monoallelic (n=3)], LRRK2 (n=7), GBA (n=7), or PARK7/DJ1 [biallelic (n=1) and monoallelic (n=2)]. Twenty-five of the mutation carriers had PD and five did not. Data were also analyzed from 19 patients with idiopathic PD and 16 control participants. α-Syn deposition varied as a function of genotype (F=16.7, P< 0.0001). It was above the control range in 100% of subjects with SNCA mutations, 100% with LRRK2 mutations, 95% with idiopathic PD, 83% with GBA mutations, and 0% with biallelic PRKN mutations. α-Syn deposition in the biallelic PRKN group was significantly higher than in the control group. In addition, patients with biallelic PRKN mutations had higher α-syn deposition than their unaffected siblings. Individuals with SNCA, DJ-1, LRRK2, or GBA mutations have substantial intraneuronal α-syn deposition in sympathetic noradrenergic nerves in skin biopsies, whereas those with biallelic PRKN mutations do not. Biallelic PRKN patients may have mildly increased α-syn deposition compared with control subjects. © 2021 International Parkinson and Movement Disorder Society.

Frequency of mutations in PRKN, PINK1, and DJ1 in Patients With Early-Onset Parkinson Disease from neighboring countries in Central Europe

IntroductionApproximately 10% of patients with Parkinson disease (PD) present with early-onset disease (EOPD), defined as diagnosis before 50 years of age. Genetic factors are known to contribute to EOPD, with most commonly observed mutations in PRKN, PINK1, and DJ1 genes. The aim of our study was to analyze the frequency of PRKN, PINK1, and DJ1 mutations in an EOPD series from 4 neighboring European countries: Czech Republic, Germany, Poland, and Ukraine. MethodsDiagnosis of PD was made based on UK Brain Bank diagnostic criteria in departments experienced in movement disorders (1 from Czech Republic, 1 from Germany, 9 from Poland, and 3 from Ukraine). EOPD was defined as onset at or before 50 years of age. Of the 541 patients recruited to the study, 11 were Czech, 38 German, 476 Polish, and 16 Ukrainian. All cohorts were fully screened with Sanger sequencing for PRKN, PINK1, and DJ1 and multiplex ligation-dependent probe amplification for exon dosage. ResultsPRKN homozygous or double heterozygous mutations were identified in 17 patients: 1 Czech (9.1%), 1 German (2.6%), 14 Polish (2.9%), and 1 Ukrainian (6.3%). PINK1 homozygous mutations were only identified in 3 Polish patients (0.6%). There were no homozygous or compound heterozygous DJ1 mutations in analyzed subpopulations. One novel variant in PRKN was identified in the Ukrainian series. ConclusionIn the analyzed cohorts, mutations in the genes PRKN, PINK1, and DJ1 are not frequently observed.

Genotype-Phenotype Relations for the Atypical Parkinsonism Genes: MDSGene Systematic Review.

This Movement Disorder Society Genetic mutation database Systematic Review focuses on monogenic atypical parkinsonism with mutations in the ATP13A2, DCTN1, DNAJC6, FBXO7, SYNJ1, and VPS13C genes. We screened 673 citations and extracted genotypic and phenotypic data for 140 patients (73 families) from 77 publications. In an exploratory fashion, we applied an automated classification procedure via an ensemble of bootstrap-aggregated (“bagged”) decision trees to distinguish these 6 forms of monogenic atypical parkinsonism and found a high accuracy of 86.5% (95% CI, 86.3%–86.7%) based on the following 10 clinical variables: age at onset, spasticity and pyramidal signs, hypoventilation, decreased body weight, minimyoclonus, vertical gaze palsy, autonomic symptoms, other nonmotor symptoms, levodopa response quantification, and cognitive decline. Comparing monogenic atypical with monogenic typical parkinsonism using 2063 data sets from Movement Disorder Society Genetic mutation database on patients with SNCA, LRRK2, VPS35, Parkin, PINK1, and DJ-1 mutations, the age at onset was earlier in monogenic atypical parkinsonism (24 vs 40 years; P = 1.2647 × 10−12) and levodopa response less favorable than in patients with monogenic typical presentations (49% vs 93%). In addition, we compared monogenic to nonmonogenic atypical parkinsonism using data from 362 patients with progressive supranuclear gaze palsy, corticobasal degeneration, multiple system atrophy, or frontotemporal lobar degeneration. Although these conditions share many clinical features with the monogenic atypical forms, they can typically be distinguished based on their later median age at onset (64 years; IQR, 57–70 years). In conclusion, age at onset, presence of specific signs, and degree of levodopa response inform differential diagnostic considerations and genetic testing indications in atypical forms of parkinsonism.

Oxidative stress factors in Parkinson's disease.

Parkinson’s disease (PD) is the second most common cause of neurodegeneration. Over the last two decades, various hypotheses have been proposed to explain the etiology of PD. Among these is the oxidant-antioxidant theory, which asserts that local and systemic oxidative damage triggered by reactive oxygen species and other free radicals may promote dopaminergic neuron degeneration. Excessive reactive oxygen species formation, one of the underlying causes of pathology in the course of PD has been evidenced by various studies showing that oxidized macromolecules including lipids, proteins, and nucleic acids accumulate in brain tissues of PD patients. DNA oxidation may produce various lesions in the course of PD. Mutations incurred as a result of DNA oxidation may further enhance reactive oxygen species production in the brains of PD patients, exacerbating neuronal loss due to defects in the mitochondrial electron transport chain, antioxidant depletion, and exposure to toxic oxidized dopamine. The protein products of SNCA, PRKN, PINK1, DJ1, and LRRK2 genes are associated with disrupted oxidoreductive homeostasis in PD. SNCA is the first gene linked with familial PD and is currently known to be affected by six mutations correlated with the disorder: A53T, A30P, E46K, G51D, H50Q and A53E. PRKN encodes Parkin, an E3 ubiquitin ligase which mediates the proteasome degradation of redundant and disordered proteins such as glycosylated α-synuclein. Over 100 mutations have been found among the 12 exons of PRKN. PINK1, a mitochondrial kinase highly expressed in the brain, may undergo loss of function mutations which constitute approximately 1–8% of early onset PD cases. More than 50 PD-promoting mutations have been found in PINK1. Mutations in DJ-1, a neuroprotective protein, are a rare cause of early onset PD and constitute only 1% of cases. Around 20 mutations have been found in DJ1 among PD patients thus far. Mutations in the LRRK2 gene are the most common known cause of familial autosomal dominant PD and sporadic PD. Treatment of PD patients, especially in the advanced stages of the disease, is very difficult. The first step in managing progressive PD is to optimize dopaminergic therapy by increasing the doses of dopamine agonists and L-dopa. The next step is the introduction of advanced therapies, such as deep brain stimulation. Genetic factors may influence the response to L-dopa and deep brain stimulation therapy and the regulation of oxidative stress. Consequently, research into minimally invasive surgical interventions, as well as therapies that target the underlying etiology of PD is warranted.

"Analysis of the Associated Mutations of DJ-1 Gene to Parkinson’s Patients in Vietnam"

The exact causes of Parkinson's disease (PD) are currently unknown, but studies have shown that the environment and genetics are the two factors that play the biggest role in Parkinson's disease. DJ-1 gene (belong to the PARK genes) is known as the main cause of Parkinson's disease in populations. In Vietnam, the evaluation of DJ-1 gene mutation frequency in patients is necessary to clarify the pathogenesis and genetic mechanisms of this disease. In this research, we identified the frequency mutations of the DJ-1 gene in Vietnamese PD patients. The results showed that we detected some DJ-1 mutations at exon 5 and exon 7. Interestingly, Ala86Gly and Gln95Leu mutations of exon 5 and His138Pro of exon 7 are found, which leads to a change in amino acid sequence and possibly a change in a functional protein. In addition, out of more than 20 heterozygous or homozygous mutations occurring in the intron regions 4 and 5, we found that 3 homozygous mutations occurred frequently in both patient and control. The data of mutation analysis has shown the ambiguous and unforeseeable meanings; however, they possibly associated with the mutation of PD. Therefore, the study of our next will focus on the relationship between these mutations with some clinical symptoms in patients.

Profiling Non-motor Symptoms in Monogenic Parkinson's Disease.

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the elder population, pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra. While the precise mechanisms underlying the pathogenesis of PD remain unknown, various genetic factors have been proved to be associated with PD. To date, at least 23 loci and 19 disease-causing genes for PD have been identified. Although monogenic (often familial) cases account for less than 5% of all PD patients, exploring the phenotypes of monogenic PD can help us understand the disease pathogenesis and progression. Primary motor symptoms are important for PD diagnosis but only detectable at a relatively late stage. Despite typical motor symptoms, various non-motor symptoms (NMS) including sensory complaints, mental disorders, autonomic dysfunction, and sleep disturbances also have negative impacts on the quality of life in PD patients and pose major challenges for disease management. NMS is common in all stages of the PD course. NMS can occur long before the onset of PD motor symptoms or can present in the middle or late stage of the disease accompanied by motor symptoms. Therefore, the profiling and characterization of NMS in monogenic PD may help the diagnosis and differential diagnosis of PD, which thereby can execute early intervention to delay the disease progression. In this review, we summarize the characteristics, clinical phenotypes, especially the NMS of monogenic PD patients carrying mutations of SNCA, LRRK2, VPS35, Parkin, PINK1, DJ-1, and GBA. The clinical implications of this linkage between NMS and PD-related genes are also discussed.

The Links between Parkinson's Disease and Cancer.

Epidemiologic studies indicate a decreased incidence of most cancer types in Parkinson’s disease (PD) patients. However, some neoplasms are associated with a higher risk of occurrence in PD patients. Both pathologies share some common biological pathways. Although the etiologies of PD and cancer are multifactorial, some factors associated with PD, such as α-synuclein aggregation; mutations of PINK1, PARKIN, and DJ-1; mitochondrial dysfunction; and oxidative stress can also be involved in cancer proliferation or cancer suppression. The main protein associated with PD, i.e., α-synuclein, can be involved in some types of neoplastic formations. On the other hand, however, its downregulation has been found in the other cancers. PINK1 can act as oncogenic or a tumor suppressor. PARKIN dysfunction may lead to some cancers’ growth, and its expression may be associated with some tumors’ suppression. DJ-1 mutation is involved in PD pathogenesis, but its increased expression was found in some neoplasms, such as melanoma or breast, lung, colorectal, uterine, hepatocellular, and nasopharyngeal cancers. Both mitochondrial dysfunction and oxidative stress are involved in PD and cancer development. The aim of this review is to summarize the possible associations between PD and carcinogenesis.

Andquot;Analysis of the Associated Mutations of DJ-1 Gene to Parkinsonandrsquo;s Patients in Vietnamandquot;

The exact causes of Parkinson's disease (PD) are currently unknown, but studies have shown that the environment and genetics are the two factors that play the biggest role in Parkinson's disease. DJ-1 gene (belong to the PARK genes) is known as the main cause of Parkinson's disease in populations. In Vietnam, the evaluation of DJ-1 gene mutation frequency in patients is necessary to clarify the pathogenesis and genetic mechanisms of this disease. In this research, we identified the frequency mutations of the DJ-1 gene in Vietnamese PD patients. The results showed that we detected some DJ-1 mutations at exon 5 and exon 7. Interestingly, Ala86Gly and Gln95Leu mutations of exon 5 and His138Pro of exon 7 are found, which leads to a change in amino acid sequence and possibly a change in a functional protein. In addition, out of more than 20 heterozygous or homozygous mutations occurring in the intron regions 4 and 5, we found that 3 homozygous mutations occurred frequently in both patient and control. The data of mutation analysis has shown the ambiguous and unforeseeable meanings; however, they possibly associated with the mutation of PD. Therefore, the study of our next will focus on the relationship between these mutations with some clinical symptoms in patients.

Deletion of DJ-1 in rats affects protein abundance and mitochondrial function at the synapse

DJ-1 is a multifunctional protein affecting different biological and cellular processes. In addition, DJ-1 has roles in regulating mitochondrial function. Loss-of-function mutations in DJ-1 were found to cause an autosomal recessive form of Parkinson’s disease. One of the main pathological features of PD is loss of dopamine neurons in the nigrostriatal pathway. DJ-1 knockout (KO) rats exhibit progressive nigral neurodegeneration with about 50% dopaminergic cell loss at 8 months of age. In order to assess the effects of DJ-1 deficiency on neuronal mitochondria prior to neuron loss, we performed proteomic analysis of synaptic mitochondria isolated from the striatum, the location of nigrostriatal pathway nerve terminals, of 3-month-old DJ-1 KO rats. In total, 371 mitochondrial proteins were quantified, and of these 76 were differentially expressed in DJ-1 KO rats. Proteins perturbed by the loss of DJ-1 were involved in several mitochondrial functional pathways, including the tricarboxylic acid cycle and electron transport chain. Thus, synaptic mitochondrial respiration was measured and showed a significant change due to DJ-1 deficiency. The dataset generated here highlights the role of synaptic mitochondria in PD associated with DJ-1. This study improves our understanding of DJ-1 effects in a complex tissue environment and the synaptic mitochondrial changes that accompany its loss.

Characterization of Recessive Parkinson Disease in a Large Multicenter Study.

Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1,587 cases. Mutations were found in 14.1% of patients; 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians, whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. ANN NEUROL 2020;88:843-850.

The Role of Oxidative Stress in Parkinson's Disease.

Parkinson’s disease (PD) is caused by progressive neurodegeneration of dopaminergic (DAergic) neurons with abnormal accumulation of α-synuclein in substantia nigra (SN). Studies have suggested the potential involvement of dopamine, iron, calcium, mitochondria and neuroinflammation in contributing to overwhelmed oxidative stress and neurodegeneration in PD. Function studies on PD-causative mutations of SNCA, PRKN, PINK1, DJ-1, LRRK2, FBXO7 and ATP13A2 further indicate the role of oxidative stress in the pathogenesis of PD. Therefore, it is reasonable that molecules involved in oxidative stress, such as DJ-1, coenzyme Q10, uric acid, 8-hydroxy-2’-deoxyguanosin, homocysteine, retinoic acid/carotenes, vitamin E, glutathione peroxidase, superoxide dismutase, xanthine oxidase and products of lipid peroxidation, could be candidate biomarkers for PD. Applications of antioxidants to modulate oxidative stress could be a strategy in treating PD. Although a number of antioxidants, such as creatine, vitamin E, coenzyme Q10, pioglitazone, melatonin and desferrioxamine, have been tested in clinical trials, none of them have demonstrated conclusive evidence to ameliorate the neurodegeneration in PD patients. Difficulties in clinical studies may be caused by the long-standing progression of neurodegeneration, lack of biomarkers for premotor stage of PD and inadequate drug delivery across blood–brain barrier. Solutions for these challenges will be warranted for future studies with novel antioxidative treatment in PD patients.

Reader response: Peripheral synucleinopathy in a DJ1 patient with Parkinson disease, cataracts, and hearing loss.

We read with interest the article by Narendra et al.1 that described a patient with Parkinson disease (PD) and young-onset bilateral cataracts associated with compound heterozygous DJ1 (PARK7) mutations. This observation confirms a suspected association between young-onset cataracts and DJ1-PD that was previously reported in 2 other cases.2,3 We report here an additional case that further strengthens this genotype-phenotype correlation and indicates that DJ1 mutations should be suspected in PD cases with young-onset cataracts.

Editors' note: Peripheral synucleinopathy in a DJ1 patient with Parkinson disease, cataracts, and hearing loss

In their article, Narendra et al. reported the case of a 35-year-old man with novel compound heterozygous DJ1 mutations who presented with early-onset Parkinson disease (PD) and was found to have autonomic peripheral synucleinopathy and impaired olfaction. They proposed that the clinical triad of early-onset PD, cataracts, and sensorineural hearing loss seen in this patient may be specific for DJ1. In response, Drs. Namnah et al. referenced 2 other published cases that reported a similar association and report another patient of Iranian-Jewish ancestry with young-onset cataracts and PD with DJ1 mutations, suggesting that young-onset cataracts in PD should direct clinicians to DJ1 testing. Responding to this comment, Narendra et al. note that the patient reported by Namnah et al.—besides substantiating their conclusion—also had both lower and upper motor neuron signs—another atypical PD feature seen in some DJ1 patients. They also note that 2 of the reported patients with Iranian-Jewish ancestry shared a mutation with another reported family of Iranian-Jewish descent, indicating a founder effect in this population. This exchange highlights the enduring importance of meticulously characterized case reports in modern neurology to strengthen genotype-phenotype correlations, particularly in relatively rare genetic diseases. In their article, Narendra et al. reported the case of a 35-year-old man with novel compound heterozygous DJ1 mutations who presented with early-onset Parkinson disease (PD) and was found to have autonomic peripheral synucleinopathy and impaired olfaction. They proposed that the clinical triad of early-onset PD, cataracts, and sensorineural hearing loss seen in this patient may be specific for DJ1. In response, Drs. Namnah et al. referenced 2 other published cases that reported a similar association and report another patient of Iranian-Jewish ancestry with young-onset cataracts and PD with DJ1 mutations, suggesting that young-onset cataracts in PD should direct clinicians to DJ1 testing. Responding to this comment, Narendra et al. note that the patient reported by Namnah et al.—besides substantiating their conclusion—also had both lower and upper motor neuron signs—another atypical PD feature seen in some DJ1 patients. They also note that 2 of the reported patients with Iranian-Jewish ancestry shared a mutation with another reported family of Iranian-Jewish descent, indicating a founder effect in this population. This exchange highlights the enduring importance of meticulously characterized case reports in modern neurology to strengthen genotype-phenotype correlations, particularly in relatively rare genetic diseases.