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There has been tremendous progress toward understanding the genetic basis of Parkinson’s disease and related movement disorders. We summarize the genetic, clinical and pathological findings of autosomal dominant disease linked to mutations in SNCA , LRRK2 , ATXN2 , ATXN3 , MAPT, GCH1, DCTN1 and VPS35 . We then discuss the identification of mutations in PARK2 , PARK7 , PINK1 , ATP13A2 , FBXO7 , PANK2 and PLA2G6 genes. In particular we discuss the clinical and pathological characterization of these forms of disease, where neuropathology has been important in the likely coalescence of pathways highly relevant to typical PD. In addition to the identification of the causes of monogenic forms of PD, significant progress has been made in defining genetic risk loci for PD; we discuss these here, including both risk variants at LRRK2 and GBA , in addition to discussing the results of recent genome-wide association studies and their implications for PD. Finally, we discuss the likely path of genetic discovery in PD over the coming period and the implications of these findings from a clinical and etiological perspective.

Microglia are the immune effector cells of the brain playing critical roles in immune surveillance and neuroprotection in healthy conditions, while they can sustain neuroinflammatory and neurotoxic processes in neurodegenerative diseases, including Parkinson’s disease (PD). Although the precise triggers of PD remain obscure, causative genetic mutations, which aid in the identification of molecular pathways underlying the pathogenesis of idiopathic forms, represent 10% of the patients. Among the inherited forms, loss of function of  PARK7 , which encodes the protein DJ-1, results in autosomal recessive early-onset PD. Yet, although protection against oxidative stress is the most prominent task ascribed to DJ-1, the underlying mechanisms linking DJ-1 deficiency to the onset of PD are a current matter of investigation. This review provides an overview of the role of DJ-1 in neuroinflammation, with a special focus on its functions in microglia genetic programs and immunological traits. Furthermore, it discusses the relevance of targeting dysregulated pathways in microglia under DJ-1 deficiency and their importance as therapeutic targets in PD. Lastly, it addresses the prospect to consider DJ-1, detected in its oxidized form in idiopathic PD, as a biomarker and to take into account DJ-1-enhancing compounds as therapeutics dampening oxidative stress and neuroinflammation.

DJ‐1, also known as Parkinson's disease protein 7 (Park7), is a multifunctional protein that regulates oxidative stress and mitochondrial function. Dysfunction of DJ‐1 is implicated in the pathogenesis of Parkinson's disease (PD). Hyperhomocysteinemia is associated with an increased risk of PD. Here we show that homocysteine thiolactone (HTL), a reactive thioester of homocysteine (Hcy), covalently modifies DJ‐1 on the lysine 182 (K182) residue in an age‐dependent manner. The N‐homocysteinylation (N‐hcy) of DJ‐1 abolishes its neuroprotective effect against oxidative stress and mitochondrial dysfunction, exacerbating cell toxicity. Blocking the N‐hcy of DJ‐1 restores its protective effect. These results indicate that the N‐hcy of DJ‐1 abolishes its neuroprotective effect and promotes the progression of PD. Inhibiting the N‐hcy of DJ‐1 may exert neuroprotective effect against PD. N‐homocysteinylation of DJ‐1 by HTL promotes neurodegeneration.

Parkinson’s disease (PD) is a common movement disorder associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Mutations in the PD-associated gene PARK7 alter the structure and function of the encoded protein DJ-1, and the resulting autosomal recessively inherited disease increases the risk of developing PD. DJ-1 was first discovered in 1997 as an oncogene and was associated with early-onset PD in 2003. Mutations in DJ-1 account for approximately 1% of all recessively inherited early-onset PD occurrences, and the functions of the protein have been studied extensively. In healthy subjects, DJ-1 acts as an antioxidant and oxidative stress sensor in several neuroprotective mechanisms. It is also involved in mitochondrial homeostasis, regulation of apoptosis, chaperone-mediated autophagy (CMA), and dopamine homeostasis by regulating various signaling pathways, transcription factors, and molecular chaperone functions. While DJ-1 protects neurons against damaging reactive oxygen species, neurotoxins, and mutant α-synuclein, mutations in the protein may lead to inefficient neuroprotection and the progression of PD. As current therapies treat only the symptoms of PD, the development of therapies that directly inhibit oxidative stress-induced neuronal cell death is critical. DJ-1 has been proposed as a potential therapeutic target, while oxidized DJ-1 could operate as a biomarker for PD. In this paper, we review the role of DJ-1 in the pathogenesis of PD by highlighting some of its key neuroprotective functions and the consequences of its dysfunction.

Loss-of-function mutations in DJ-1 are associated with autosomal recessive early onset Parkinson’s disease (PD), yet the underlying pathogenic mechanism remains elusive. Here we demonstrate that DJ-1 localized to the mitochondria-associated membrane (MAM) both in vitro and in vivo. In fact, DJ-1 physically interacts with and is an essential component of the IP3R3-Grp75-VDAC1 complexes at MAM. Loss of DJ-1 disrupted the IP3R3-Grp75-VDAC1 complex and led to reduced endoplasmic reticulum (ER)-mitochondria association and disturbed function of MAM and mitochondria in vitro. These deficits could be rescued by wild-type DJ-1 but not by the familial PD-associated L166P mutant which had demonstrated reduced interaction with IP3R3-Grp75. Furthermore, DJ-1 ablation disturbed calcium efflux-induced IP3R3 degradation after carbachol treatment and caused IP3R3 accumulation at the MAM in vitro. Importantly, similar deficits in IP3R3-Grp75-VDAC1 complexes and MAM were found in the brain of DJ-1 knockout mice in vivo. The DJ-1 level was reduced in the substantia nigra of sporadic PD patients, which was associated with reduced IP3R3-DJ-1 interaction and ER-mitochondria association. Together, these findings offer insights into the cellular mechanism in the involvement of DJ-1 in the regulation of the integrity and calcium cross-talk between ER and mitochondria and suggests that impaired ER-mitochondria association could contribute to the pathogenesis of PD.

BackgroundLiver fibrosis can progress to cirrhosis and hepatic carcinoma without treatment. CircDCBLD2 was found to be downregulated in liver fibrosis. However, the precise underlying mechanism requires further investigation.MethodsqRT-PCR, Western blot, and immunohistochemistry assays were used to detect the related molecule levels. HE, Masson’s trichrome, and Sirius Red staining were used to assess the pathological changes in mice’s liver tissues. Flow cytometric analysis and commercial kit were used to assess the levels of lipid reactive oxygen species (ROS), malonaldehyde (MDA), glutathione (GSH), and iron. Cell viability was assessed by MTT. Immunoprecipitation was used to study the ubiquitination of PARK7. Mitophagy was determined by immunostaining and confocal imaging. RIP and Co-IP assays were used to assess the interactions of circDCBLD2/HuR, HuR/STUB1, and STUB1/PARK7. Fluorescence in situ hybridization and immunofluorescence staining were used to assess the co-localization of circDCBLD2 and HuR.ResultsCircDCBLD2 was downregulated, whereas PARK7 was upregulated in liver fibrosis. Ferroptosis activators increased circDCBLD2 while decreasing PARK7 in hepatic stellate cells (HSCs) and mice with liver fibrosis. CircDCBLD2 overexpression reduced cell viability and GSH, PARK7, and GPX4 expression in erastin-treated HSCs while increasing MDA and iron levels, whereas circDCBLD2 knockdown had the opposite effect. CircDCBLD2 overexpression increased STUB1-mediated PARK7 ubiquitination by promoting HuR-STUB1 binding and thus increasing STUB1 mRNA stability. PARK7 overexpression or HuR knockdown reversed the effects of circDCBLD2 overexpression on HSC activation and ferroptosis. CircDCBLD2 reduced liver fibrosis in mice by inhibiting PARK7.ConclusionCircDCBLD2 overexpression increased PARK7 ubiquitination degradation by upregulating STUB1 through its interaction with HuR, inhibiting HSC activation and promoting HSC ferroptosis, ultimately enhancing liver fibrosis.

Neurodegenerative diseases are a growing burden, and there is an urgent need for better biomarkers for diagnosis, prognosis, and treatment efficacy. Structural and functional brain alterations are reflected in the protein composition of cerebrospinal fluid (CSF). Alzheimer's disease (AD) patients have higher CSF levels of tau, but we lack knowledge of systems‐wide changes of CSF protein levels that accompany AD. Here, we present a highly reproducible mass spectrometry (MS)‐based proteomics workflow for the in‐depth analysis of CSF from minimal sample amounts. From three independent studies (197 individuals), we characterize differences in proteins by AD status (> 1,000 proteins, CV < 20%). Proteins with previous links to neurodegeneration such as tau, SOD1, and PARK7 differed most strongly by AD status, providing strong positive controls for our approach. CSF proteome changes in Alzheimer's disease prove to be widespread and often correlated with tau concentrations. Our unbiased screen also reveals a consistent glycolytic signature across our cohorts and a recent study. Machine learning suggests clinical utility of this proteomic signature. Synopsis A robust proteomic workflow quantifies more than 1,000 proteins in cerebrospinal fluid and reveals an Alzheimer's Disease‐associated signature of more than 20 proteins across three independent cohorts. These include tau, superoxide dismutase 1, PARK7, YKL‐40 and novel biomarker candidates. Proteomics workflow for quantification of more than 1,000 proteins from microliters of cerebrospinal fluid. More than 20 proteins consistently associated with Alzheimer's Disease across three cohorts comprising about 200 individuals in total. Alzheimer's Disease CSF signature of Tau, SOD1, PARK7, YKL‐40, and glycolysis‐related proteins. Graphical Abstract A robust proteomic workflow quantifies more than 1,000 proteins in cerebrospinal fluid and reveals an Alzheimer's Disease‐associated signature of more than 20 proteins across three independent cohorts. These include tau, superoxide dismutase 1, PARK7, YKL‐40 and novel biomarker candidates.

Background and Purpose Multiple system atrophy (MSA) is a progressive, adult‐onset neurodegenerative disorder clinically characterized by combinations of autonomic failure, parkinsonism, cerebellar ataxia and pyramidal signs. Although a few genetic factors have been reported to contribute to the disease, its mutational profiles have not been systemically studied. Methods To address the genetic profiles of clinically diagnosed MSA patients, exome sequencing and triplet repeat detection was conducted in 205 MSA patients, including one familial case. The pathogenicity of variants was determined according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. Results In the familial patient, a novel heterozygous COQ2 pathogenic variant (p.Ala351Thr) was identified in the MSA pedigree. In the sporadic patients, 29 pathogenic variants were revealed in 21 genes, and the PARK7 p.Ala104Thr variant was significantly associated with MSA (p = 0.0018). Moreover, burden tests demonstrated that the pathogenic variants were enriched in cerebellar ataxia‐related genes in patients. Furthermore, repeat expansion analyses revealed that two patients carried the pathogenic CAG repeat expansion in the CACNA1A gene (SCA6), one patient carried the (ACAGG)exp/(ACAGG)exp expansion in RFC1 and one carried the GAA‐pure expansion in FGF14 gene. Conclusion In conclusion, a novel COQ2 pathogenic variant was identified in a familial MSA patient, and repeat expansions in CACNA1A, RFC1 and FGF14 gene were detected in four sporadic patients. Moreover, a PARK7 variant and the burden of pathogenic variants in cerebellar ataxia‐related genes were associated with MSA.

Diffuse large B‐cell lymphoma (DLBCL) is difficult to treat due to the high recurrence rate and therapy intolerance, so finding potential therapeutic targets for DLBCL is critical. FK506‐binding protein 3 (FKBP3) contributes to the progression of various cancers and is highly expressed in DLBCL, but the role of FKBP3 in DLBCL and its mechanism are not clear. Our study demonstrated that FKBP3 aggravated the proliferation and stemness of DLBCL cells, and tumour growth in a xenograft mouse model. The interaction between FKBP3 and parkinsonism associated deglycase (PARK7) in DB cells was found using co‐immunoprecipitation assay. Knockdown of FKBP3 enhanced the degradation of PARK7 through increasing its ubiquitination modification. Forkhead Box O3 (FOXO3) belongs to the forkhead family of transcription factors and inhibits DLBCL, but the underlying mechanism has not been reported. We found that FOXO3 bound the promoter of FKBP3 and then suppressed its transcription, eventually weakening DLBCL. Mechanically, FKBP3 activated Wnt/β‐catenin signalling pathway mediated by PARK7. Together, FKBP3 increased PARK7 and then facilitated the malignant phenotype of DLBCL through activating Wnt/β‐catenin pathway. These results indicated that FKBP3 might be a potential therapeutic target for the treatment of DLBCL.

This work comprehends the development and characterization of a carbon black-based electrode modified with Au microflowers to increase its effect as a capacitance biosensor for the determination of PARK7/DJ-1. Due to its high surface-to-volume ratio and biocompatibility, Au particles are suitable for antibody binding, and by monitoring surface capacitance, it is possible to identify the immune-pair interaction. Au microflowers allowed the adequate immobilization of Parkinsonian-related proteins: PARK7/DJ-1 and its antibody. The protein is associated with several antioxidant mechanisms, but its abnormal concentrations or mutations can be the cause of the loss of dopaminergic neurons, leading to Parkinson’s disease. The device was characterized by scanning electron microscopy and cyclic voltammetry, revealing the flower-like structures and the electrochemically-interest enhancements they provide, such as increased heterogeneous electron transfer rate coefficient and electroactive area. The self-assembled monolayers of different molecules were optimized with the aid of 2 2 central composite experiments and a linear calibration curve was obtained between 0.700 and 120 ng mL -1 of PARK7/DJ-1, with a limit of detection of 0.207 ng mL -1 . The data confirms that the addition of Au microflowers enhanced the electrochemical signal of the device, as well as allowed for the determination of an early stage Parkinson’s disease biomarker with appreciable analytical performance. Graphical Abstract