更新于：2024-11-01

PRKN

更新于：2024-11-01

基本信息

别名

AR-JP、E3 ubiquitin-protein ligase parkin、PARK2

+ [7]

简介

Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins (PubMed:10888878, PubMed:10973942, PubMed:11431533, PubMed:12150907, PubMed:12628165, PubMed:15105460, PubMed:16135753, PubMed:21376232, PubMed:21532592, PubMed:23754282, PubMed:23620051, PubMed:24660806, PubMed:24751536, PubMed:32047033, PubMed:29311685, PubMed:22396657). Substrates include SYT11 and VDAC1 (PubMed:32047033, PubMed:29311685). Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and AIMP2 (PubMed:10888878, PubMed:10973942, PubMed:11431533, PubMed:12150907, PubMed:12628165, PubMed:15105460, PubMed:16135753, PubMed:21376232, PubMed:21532592, PubMed:23754282, PubMed:23620051, PubMed:24660806, PubMed:24751536, PubMed:22396657). Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context (PubMed:19229105, PubMed:20889974, PubMed:25621951, PubMed:32047033, PubMed:25474007). Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'-linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation (PubMed:17846173, PubMed:19229105). Mediates 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation (PubMed:11431533, PubMed:11590439, PubMed:15105460, PubMed:19229105, PubMed:15728840). Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy (PubMed:20889974). Protects against mitochondrial dysfunction during cellular stress, by acting downstream of PINK1 to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components (PubMed:32047033, PubMed:19029340, PubMed:19966284, PubMed:23620051, PubMed:24896179, PubMed:25527291, PubMed:18957282, PubMed:21376232, PubMed:22396657, PubMed:24660806, PubMed:25474007, PubMed:24784582, PubMed:11439185, PubMed:22082830, PubMed:23933751). Depending on the severity of mitochondrial damage and/or dysfunction, activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to regulating mitochondrial dynamics and eliminating severely damaged mitochondria via mitophagy (PubMed:32047033, PubMed:19029340, PubMed:19801972, PubMed:19966284, PubMed:23620051, PubMed:24896179, PubMed:25527291, PubMed:21376232, PubMed:22396657, PubMed:11439185, PubMed:22082830, PubMed:23933751, PubMed:33499712). Activation and recruitment onto the outer membrane of damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated phosphorylation of both PRKN and ubiquitin (PubMed:24660806, PubMed:25474007, PubMed:24784582, PubMed:25527291). After mitochondrial damage, functions with PINK1 to mediate the decision between mitophagy or preventing apoptosis by inducing either the poly- or monoubiquitination of VDAC1, respectively; polyubiquitination of VDAC1 promotes mitophagy, while monoubiquitination of VDAC1 decreases mitochondrial calcium influx which ultimately inhibits apoptosis (PubMed:32047033). When cellular stress results in irreversible mitochondrial damage, promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1, MFN1 and USP30 (PubMed:19029340, PubMed:19966284, PubMed:21753002, PubMed:23620051, PubMed:24896179, PubMed:25527291, PubMed:22396657, PubMed:23933751). Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to mitophagy (PubMed:25621951, PubMed:32047033). The PINK1-PRKN pathway also promotes fission of damaged mitochondria by PINK1-mediated phosphorylation which promotes the PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2 (PubMed:23620051). This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes (PubMed:23620051). Regulates motility of damaged mitochondria via the ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor neurons, this likely inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria undergoing mitophagy in the soma (PubMed:22396657). Involved in mitochondrial biogenesis via the 'Lys-48'-linked polyubiquitination of transcriptional repressor ZNF746/PARIS which leads to its subsequent proteasomal degradation and allows activation of the transcription factor PPARGC1A (PubMed:21376232). Limits the production of reactive oxygen species (ROS) (PubMed:18541373). Regulates cyclin-E during neuronal apoptosis (PubMed:12628165). In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress (PubMed:22082830). Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53 (PubMed:19801972). May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity (PubMed:11439185). May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene (PubMed:12719539).

关联

项与 PRKN 相关的药物

Parkin activators(Nine Square)

Parkin激活剂(Nine Square)

靶点

PRKN

作用机制

PRKN激活剂

在研机构

Nine Square Therapeutics, Inc.初创企业

原研机构

Nine Square Therapeutics, Inc.初创企业

在研适应症

帕金森病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

PARK2 (Black Swan Pharmaceuticals)

靶点

PRKN

作用机制

PRKN modulators

在研机构

Black Swan Pharmaceuticals, Inc.初创企业

原研机构

Black Swan Pharmaceuticals, Inc.初创企业

在研适应症

中枢神经系统疾病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

WO2022031708

专利挖掘

靶点

PRKN

作用机制-

在研机构

Prevail Therapeutics, Inc.

原研机构

Prevail Therapeutics, Inc.

在研适应症

营养和代谢疾病

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PRKN 相关的临床结果

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100 项与 PRKN 相关的转化医学

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0 项与 PRKN 相关的专利（医药）

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6,030

项与 PRKN 相关的文献（医药）

2025-04-01·Neural Regeneration Research

Differential distribution of PINK1 and Parkin in the primate brain implies distinct roles

Article

作者: Wang, Qi ; Wen, Jiayi ; Liu, Yanting ; Huang, Wei ; Chen, Xiusheng ; Xu, Ting ; Xiong, Xin ; Li, Xiaojiang ; Zhao, Xianxian ; Yang, Weili ; Li, Shihua

JOURNAL/nrgr/04.03/01300535-202504000-00028/figure1/v/2024-07-06T104127Z/r/image-tiff The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration. However, it remains largely unclear how PINK1 and Parkin are expressed in mammalian brains. This has been difficult to address because of the intrinsically low levels of PINK1 and undetectable levels of phosphorylated Parkin in small animals. Understanding this issue is critical for elucidating the in vivo roles of PINK1 and Parkin. Recently, we showed that the PINK1 kinase is selectively expressed as a truncated form (PINK1–55) in the primate brain. In the present study, we used multiple antibodies, including our recently developed monoclonal anti-PINK1, to validate the selective expression of PINK1 in the primate brain. We found that PINK1 was stably expressed in the monkey brain at postnatal and adulthood stages, which is consistent with the findings that depleting PINK1 can cause neuronal loss in developing and adult monkey brains. PINK1 was enriched in the membrane-bound fractionations, whereas Parkin was soluble with a distinguishable distribution. Immunofluorescent double staining experiments showed that PINK1 and Parkin did not colocalize under physiological conditions in cultured monkey astrocytes, though they did colocalize on mitochondria when the cells were exposed to mitochondrial stress. These findings suggest that PINK1 and Parkin may have distinct roles beyond their well-known function in mitophagy during mitochondrial damage.

2025-03-01·Biomaterials

m7G-modified mt-tRF3b-LeuTAA regulates mitophagy and metabolic reprogramming via SUMOylation of SIRT3 in chondrocytes

Article

作者: Xu, Yiyang ; He, Aishan ; Zhong, Yanlin ; Mao, Guping ; Mo, Xiaolin ; Long, Dianbo ; Zhang, Ziji ; Deng, Zengfa ; Kang, Yan ; Zhao, Xiaoyi ; Li, Wei ; Li, Ming

N7-methylguanosine (m⁷G) modification is one of the most prevalent RNA modifications, and methyltransferase-like protein-1 (METTL1) is a key component of the m⁷G methyltransferase complex. METTL1-catalyzed m⁷G as a new RNA modification pathway that regulates RNA structure, biogenesis, and cell migration. Increasing evidence indicates that m⁷G modification has been implicated in the pathophysiological process of osteoarthritis (OA). However, the underlying molecular mechanisms of m⁷G modification remains incompletely elucidated during the progression of OA. Here we found that METTL1 and m⁷G levels were markedly increased in OA chondrocytes. In addition, METTL1-mediated m⁷G modification upregulated mt-tRF3b-LeuTAA expression to exacerbate chondrocyte degeneration. Mechanistically, mt-tRF3b-LeuTAA decreased the SUMO-specific protease 1 (SENP1) protein expression and upregulated the level of sirtuin 3 (SIRT3) SUMOylation to inhibit PTEN induced kinase 1 (PINK1)/Parkin-mediated mitochondrial mitophagy. Intra-articular injection of PMC-tRF3b-LeuTAA inhibitor (Polyamidoamine-polyethylene glycol surface-modified with Minimal self-peptides and Chondrocyte-affinity peptides, PMC) attenuated destabilization of the medial meniscus (DMM) mouse cartilage degeneration in vivo. Our study demonstrates that METTL1/m⁷G/mt-tRF3b-LeuTAA axis accelerate cartilage degradation by inhibiting mitophagy and promoting mitochondrial dysfunction through SIRT3 SUMOylation, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for OA treatment.

2025-01-01·Journal of Ethnopharmacology

Po-Ge-Jiu-Xin decoction alleviate sepsis-induced cardiomyopathy via regulating phosphatase and tensin homolog-induced putative kinase 1 /parkin-mediated mitophagy

Article

作者: Dong, Chen ; Wang, Zheng ; Jiang, Bing ; Wang, Yanjun ; Wang, Yu ; Zhang, Zheng ; Zhou, Dan ; Dong, Kang ; Miao, Kaihui

ETHNOPHARMACOLOGICAL RELEVANCESepsis is a life-threatening systemic syndrome usually accompanied by myocardial dysfunction. Po-Ge-Jiu-Xin decoction (PGJXD), a traditional Chinese prescription medicine, has been used clinically to treat cardiovascular disease including heart failure, sepsis-induced cardiomyopathy (SIC) and even septic shock. Previous clinical studies suggested PGJXD has shown promising results in improving cardiac function and treating heart failure in sepsis. However, more research is needed to elucidate the mechanisms underlying PGJXD's therapeutic effects in sepsis-induced cardiomyopathy.MATERIALS AND METHODSInitially, we identified the major compounds of PGJXD through ultra-performance liquid chromatography-mass spectrometry technology analysis. We established in a SIC rat model using cecal ligation and puncture(CLP) and treated by PGJXD and levosimendan. We evaluated pathological damage by hematoxylin and eosin staining and measured serum myocardial injury biomarkers. Myocardial apoptosis was detected by Tunel staining and quantifying specific biomarker protein levels. Subsequently, we evaluated myocardium mitochondrial quality using Transmission electron microscope (TEM), antioxidant stress indexes and tissue adenosine triphosphate(ATP) content. We detected the expression of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), parkin, LC3, and p62 using Western blotting and Quantitative real time polymerase chain reaction(qRT-PCR). (Lipopolysaccharides, LPS)-induced H9c2 cell model was established to further explore the mechanism of PGJXD on SIC. In addition to measuring cell viability, we measured mitochondrial membrane potential using JC-1 staining. Additionally, Parkin-siRNA transfected into H9c2 cells to validate whether PGJXD conducted protective effects against SIC through PINK1/Parkin-mediated mitophagy.RESULTSIt has been demonstrated that PGJXD reduced mortality in septic rat, contributed to ameliorating myocardium injury, suppressed inflammatory response and ameliorated the myocardial apoptosis. PGJXD could also alleviate mitochondrial structural abnormality, mitigated oxidative stress injury and promoted energy synthesis in CLP models. Western blotting and qRT-PCR have further confirmed that PGJXD can activate PINK1/parkin pathway-mediated mitophagy, resulting in preserving mitochondrial quality in the myocardium. Furthermore, Parkin siRNA partially reversed the beneficial effect of PGJXD on mitochondrial fission/fusion and mitophagy in vitro. Therefore, the cardioprotective effect of PGJXD is achieved by inducing PINK1/Parkin-mediated mitophagy in maintaining mitochondrial homeostasis.CONCLUSIONSThese results suggest that the potential therapeutic effect of PGJXD on cardiac dysfunction during sepsis and support its mechanism of targeted induction of PINK1-Parkin-mediated mitophagy.

项与 PRKN 相关的新闻（医药）

2024-08-01

·GlobeNewswire-Health Care

CENTOGENE Publication in Brain Journal Reveals 15% of Parkinson’s Disease Cases Are Linked to Genetic Factors

Initial data from largest international Parkinson’s disease patient cohort shows approximately 90% of these genetically confirmed patients had variants in the LRRK2 or GBA1 genes, making these individuals potential candidates to be included in gene-targeted trialsThe Rostock International Parkinson's Disease (ROPAD) Study aims to characterize the genetics of Parkinson’s disease (PD) to establish a better understanding of disease progression, diagnosis, and treatment for patients CAMBRIDGE, Mass. and ROSTOCK, Germany and BERLIN, Aug. 01, 2024 (GLOBE NEWSWIRE) -- Centogene N.V. (Nasdaq: CNTG), the essential life science partner for data-driven answers in rare and neurodegenerative diseases, today announced data from the Company’s Rostock International Parkinson's Disease (ROPAD) Study revealing the genetic factors and prevalence of Parkinson’s disease (PD). The findings from this landmark study indicate that approximately 15% of PD-related cases are tied to genetic variants, with the majority being linked to LRRK2 and GBA1. The data was published in Brain in a paper titled, “Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson’s disease study.” “Over the past five years, CENTOGENE and our more than 100 study sites around the world have worked together to diagnose Parkinson’s patients and accelerate treatment options,” said Prof. Peter Bauer, Chief Medical and Genomic Officer at CENTOGENE. “Our collaborative work clearly shows how significant of a role genetics plays in Parkinson’s disease and underscores the need to integrate genetic testing in routine care of these patients. This will not only enable access to potentially available treatments, but will de-risk and accelerate the development of gene-specific therapies – driving the future of Parkinson’s disease patient care.” The research investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap from over 12,500 patients from 16 countries who have been enrolled in CENTOGENE’s ROPAD Study. In more than 1,800 participants, a PD-relevant genetic test (PDGT) provided a positive result. This included variants linked to the LRRK2 and GBA1 genes, as well as PRKN, SNCA, and PINK1, or a combination of genetic findings in multiple genes. In the emerging era of gene-targeted PD clinical trials, the Company’s findings that approximately 15% of patients harbor potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. By capturing such genetic data, this also allows for differential genetic counselling across the spectrum of different ages at onset and family histories. The Company recently launched a ROPAD Consortium to continue driving PD research and treatment through collaborative efforts. The ROPAD Consortium will build on the vast network of neurologists, existing partnerships with non-profit organizations, and the largest genetic testing program for PD patients worldwide to streamline access to critical data, drive impactful research, and improve the potential for advancing treatment options. To find out more, email: contact.pharma@centogene.com About ROPAD The Rostock International Parkinson's Disease (ROPAD) Study is a global epidemiological study focusing on the role of genetics in Parkinson’s disease (PD). The major goal of the study is to characterize the genetics of PD to establish a better understanding of the disease etiology, diagnosis, and severity. CENTOGENE utilizes CentoCard®, the Company’s proprietary, CE-marked Dried Blood Spot (DBS) collection kit in combination with state-of-the-art sequencing technologies to screen for mutations in LRRK2 and other PD-associated genes. To date, over 18,000 participants from around the world have been tested over a five-year period. About CENTOGENE CENTOGENE’s mission is to provide data-driven, life-changing answers to patients, physicians, and pharma companies for rare and neurodegenerative diseases. We integrate multiomic technologies with the CENTOGENE Biodatabank – providing dimensional analysis to guide the next generation of precision medicine. Our unique approach enables rapid and reliable diagnosis for patients, supports a more precise physician understanding of disease states, and accelerates and de-risks targeted pharma drug discovery, development, and commercialization. Since our founding in 2006, CENTOGENE has been offering rapid and reliable diagnosis – building a network of approximately 30,000 active physicians. Our ISO, CAP, and CLIA certified multiomic reference laboratories in Germany utilize Phenomic, Genomic, Transcriptomic, Epigenomic, Proteomic, and Metabolomic datasets. This data is captured in our CENTOGENE Biodatabank, with over 850,000 patients represented from over 120 highly diverse countries, over 70% of whom are of non-European descent. To date, the CENTOGENE Biodatabank has contributed to generating novel insights for more than 300 peer-reviewed publications. By translating our data and expertise into tangible insights, we have supported over 50 collaborations with pharma partners. Together, we accelerate and de-risk drug discovery, development, and commercialization in target and drug screening, clinical development, market access and expansion, as well as offering CENTOGENE Biodata Licenses and Insight Reports to enable a world healed of all rare and neurodegenerative diseases. To discover more about our products, pipeline, and patient-driven purpose, visit www.centogene.com and follow us on LinkedIn. Contacts:Melissa HallCENTOGENECorporate Communications Press@centogene.com Lennart StreibelCENTOGENEInvestor Relations IR@centogene.com

临床研究

2024-05-20

·生物探索

STTT | 西南交通大学符雷蕾等团队合作发现缓解心肌肥大和纤维化的潜在新策略

引言Sirtuin 3（SIRT3）是一种保守的烟酰胺腺嘌呤二核苷酸（NAD+）依赖性去乙酰酶，位于线粒体中，可调节氧化应激、分解代谢和ATP产生。最近越来越多的证据表明，SIRT3通过其脱乙酰化修饰在心脏纤维化、心肌纤维化甚至心力衰竭（HF）中发挥关键作用。因此，迫切需要发现SIRT3激活剂并阐明其潜在的HF机制。2024年5月15日，西南交通大学符雷蕾、深圳大学张瑾及成都中医药大学韩波共同通讯（彭芙为第一作者）在Signal Transduction and Targeted Therapy 发表题为“2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis”的研究论文，研究通过基于结构的药物设计策略确定了一种新的SIRT3小分子激活剂（命名为2-APQC）。2-APQC在体外和体内大鼠模型中被证明可以缓解异丙肾上腺素（ISO）诱导的心脏肥大和心肌纤维化。重要的是，在SIRT3敲除小鼠中，2-APQC不能缓解HF，这表明2-APQC依赖于SIRT3的保护作用。从机制上讲，2-APQC可抑制哺乳动物雷帕霉素靶标（mTOR）-p70核糖体蛋白S6激酶（p70S6K）、c-jun N末端激酶（JNK）和转化生长因子-β（TGF-β）/Smad3通路，以改善ISO诱导的心脏肥大和心肌纤维化。基于RNA-seq分析，研究证明SIRT3-吡咯啉-5-羧酸还原酶1（PYCR1）轴与HF密切相关。通过激活PYCR1,2-APQC可增强线粒体脯氨酸代谢，抑制活性氧（ROS）-p38 丝裂原活化蛋白激酶（p38MAPK）通路，从而防止ISO诱导的线粒体氧化损伤。此外，2-APQC激活SIRT3可以促进AMP活化蛋白激酶（AMPK）-Parkin轴抑制ISO诱导的坏死。总之，研究结果表明，2-APQC是一种靶向SIRT3激活剂，通过调节线粒体稳态来缓解心肌肥大和纤维化，这可能为开发未来HF治疗的有前途的候选药物提供新的线索。心力衰竭（HF）是一种复杂的临床综合征，其特征是心脏结构和功能异常。众所周知，心肌肥大在病理性心脏重塑的进展中起着重要作用，病理性心脏重塑可表现为异常的心肌纤维化。心衰的病理机制很复杂，有待阐明。事实上，心功能不全往往伴随着线粒体氧化代谢和能量代谢异常。因此，调节线粒体代谢相关蛋白和酶以改善心脏代谢紊乱是一种很有前途的心衰治疗策略。值得注意的是，Sirtuin 3（SIRT3）是线粒体中重要的组蛋白脱乙酰酶，高度参与线粒体动力学、ROS 产生和氧化还原稳态。新兴研究表明，SIRT3可以保护心肌细胞免受肥大，缓解心肌纤维化并改善心力衰竭。此外，作为重要的表观遗传靶点，SIRT3参与线粒体蛋白的翻译后蛋白修饰和去乙酰化，以调节心血管疾病。SIRT3可以通过叉头盒O3（FOXO3）的去乙酰化来激活锰超氧化物歧化酶2（MnSOD2）和过氧化氢酶来抑制ROS的产生。由于SIRT3在心脏中的保护作用，激活SIRT3可能是治疗HF的潜在治疗策略。一系列小分子化合物已被证明可作为SIRT3激活剂或上调HF中SIRT3的表达，以达到潜在的治疗目的。例如，LCZ696通过SIRT3依赖性途径诱导MnSOD2上调，以减少压力负荷 HF 中的心肌氧化应激和细胞凋亡。此外，通过激活SIRT3，Oroxylin A可以通过调节FoxO3A的DNA结合活性来促进SIRT3介导的超氧化物歧化酶2（SOD2）基因的表达，并通过脱乙酰化提高SOD2的活性。然而，上述这些化合物对SIRT3活化的影响不是选择性的。因此，用于HF治疗的新型靶向SIRT3激活剂仍有待发现。模式图（Credit: Signal Transduction and Targeted Therapy）蛋白激酶B（Akt）是一种分子量约为 60 kDa 的丝/苏氨酸蛋白激酶，由 Akt1、Akt2 和 Akt3 组成。Thr308位点的磷酸化增加了Akt的激酶活性，通过调节各种细胞内蛋白诱导心肌肥大的发生和进展。Akt的下游调控通路之一是mTOR通路。mTOR可诱导p70S6K磷酸化，从而募集真核延伸因子4E并合成蛋白质，调节心肌肥大和心力衰竭。因此，Akt/mTOR/p70S6K信号通路在心肌肥大和心力衰竭的发生中起着重要的调节作用。PYCR1 是一种管家酶，通过催化P5C转化为脯氨酸来参与脯氨酸生物合成的最后一步。它位于线粒体中，线粒体主要参与疾病中谷氨酸向脯氨酸的转化。此外，SIRT3可以通过在K228位点直接结合和脱乙酰化 PYCR1 来增加酶活性，这意味着SIRT3的激活可能通过抑制 PYCR1 介导的氧化应激来改善心脏病。在之前的研究中，在NAD+ 结合口袋（Pocket L和Pocket U）附近发现了两个潜在的 SIRT3激活口袋。在这项研究中，靶向Pocket L，发现了一种有效的SIRT3激活剂2-APQC，它与SIRT3结合并激活。这种激活影响关键的信号通路，在体外和体内模型中有效降低 ISO 诱导的心肌肥大和纤维化大鼠心力衰竭，并证实了2-APQC在SIRT3敲除小鼠中的靶向性。根据RNA-Seq 分析，证实2-APQC可以通过激活 SIRT3-PYCR1 轴来抑制线粒体氧化应激，并通过激活AMPK-Parkin信号来抑制 ISO 诱导的坏死来改善心脏功能，从而保护心脏细胞免受ISO诱导的损伤。综上所述，这些结果表明，2-APQC是一种新型靶向小分子SIRT3激活剂，通过调节线粒体稳态来缓解心肌肥大和纤维化，这将为未来发现潜在的HF治疗候选药物提供新的线索。原文链接https://doi.org/10.1038/s41392-024-01816-1责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

siRNA寡核苷酸上市批准

2024-04-12

·GBIHealth

帕金森：新疗法已在路上

帕金森病（Parkinson's disease，简称PD）帕金森病是仅次于阿尔茨海默病（AD）的第二大神经退行性疾病，于1817年由James Parkinson医生最早描述其症状，并以他的名字命名。作为常见的中老年神经系统退行性疾病，临床表现为震颤、肌强直、姿势平衡障碍等运动症状和睡眠障碍、自主神经功能障碍、认知和精神障碍等非运动症状，中晚期阶段常伴有运动并发症，严重影响患者的生活质量。变，万物随阳气上升而萌芽生长。 “ 据统计，全球范围内约有1000多万名患者饱受帕金森病的困扰。而我国的帕金森病患者人数预计将从2005年的199万人上升到2030年的近500万人，几乎占到全球帕金森病患病人数的一半。”发病机制帕金森的主要病理变化发生在中脑黑质腹侧的致密部，该区含有大量多巴胺神经元，患者致密部神经元大量死亡，有的甚至丧失高达70%的神经元，导致多巴胺的缺乏以及动作、边缘系统等神经回路的故障。二十世纪60年代研究发现，多巴胺前体化合物左旋多巴对帕金森症有治疗效果，直到今天仍是治疗帕金森的主力药物。然而，多巴胺制剂只能缓解帕金森症状，治标不治本，且副作用较大。后续研究发现，大脑黑质的病变与α-突触核蛋白有关，这种蛋白异常积聚，形成纤维蛋白沉淀并最终导致神经细胞死亡。α-突触核蛋白是可溶性蛋白，导致其异常聚集通常伴随着免疫激活、神经炎症、线粒体功能障碍以及溶酶体和内体功能的改变。研究者发现，这些病理过程与基因密切相关。比如，具有PRKN基因突变和主要线粒体功能障碍的患者表现出一种受限的细胞丧失模式，主要局限在黑质纹状体系统中，没有典型散发性帕金森病中所见的广泛病理和非运动特征。相反，具有SNCA或GBA突变，且α-突触核蛋白病理明显的患者在早期表现出非运动特征，包括自主神经功能障碍和痴呆，可能反映了全身和大脑中的广泛病理。这些风险基因不一定与α-突触核蛋白的病理直接相关。目前已经确定七个基因作为单基因病因，其中四个导致晚发性、常染色体显性遗传疾病（即LRRK2、CHCHD2、VPS35和SNCA），三个导致早发性、常染色体隐性遗传疾病（即PARKIN、DJ1和PINK1）。第八个基因GBA的变异是帕金森病的最常见遗传风险因素。未来有望开发出针对专门靶点的治疗药物。主要治疗思路流程除多巴胺制剂之外，儿茶酚-氧位-甲基转移酶抑制剂以及单胺氧化酶B型抑制剂也是帕金森的常用药物。根据《2020年中国帕金森病治疗指南》，对早发型、晚发型帕金森病，根据主要症状的不同选择不同的治疗方案（图1）。图1.患者用药选择流程图参考来源：《2020年中国帕金森病治疗指南》；DAs：多巴胺受体激动剂；MAO-BI：单胺氧化酶B型抑制剂；COMTI：儿茶酚-O-甲级转移酶抑制剂2020年指南继续强调了多学科治疗： ①坚持综合治疗，应对帕金森病的运动症状和非运动症状采取全面综合治疗；②强调多学科治疗模式，药物治疗仍为首选，并结合手术、运动与康复、心理干预等多种治疗手段；同时，提倡在临床条件允许的情况下，组建神经内科、功能神经外科、神经心理、康复乃至社区全科医生等多学科的医生团队；③明确全程管理，目前的治疗仍以改善症状为主，不能阻止病情的发展，治疗不仅立足当前，而且需长期管理，以达到长期获益。常见药物与在研新药根据传统治疗分类和在中国获批的药品，帕金森治疗药物主要有以下几种。复方左旋多巴：恩他卡朋双多巴、多巴丝肼多巴胺受体激动剂（DAs）：溴隐亭、培高利特（已撤市）、吡贝地尔、甲磺酸-a-二氢麦角隐亭、普拉克索、罗匹尼罗和罗替高汀儿茶酚-O-甲级转移酶抑制剂（COMTI）：托卡朋和恩他卡朋单胺氧化酶B型抑制剂（MAO-BI）：雷沙吉兰和司来吉兰抗胆碱药：苯甲托品、苯海索以及苯海拉明去甲肾上腺素前体：屈昔多巴神经保护剂：单唾液酸四己糖神经节苷脂钠此外，还有左旋多巴和卡比多巴，其中卡比多巴需与左旋多巴联用。帕金森领域进展较慢，从2010年至今，美国FDA批准的能用于缓解帕金森症状的新分子实体仅4款：Acadia Pharma 的5-羟色胺2A受体反向激动剂酒石酸匹莫范色林、US WorldMeds的沙非酰胺、协和发酵麒麟的A2A受体拮抗剂伊曲茶碱以及第三代强效COMTI奥匹卡朋。奥匹卡朋已有复星医药引进中国，目前正在进行临床试验。在国内进行开发的帕金森药品见下表。来源：GBI SOURCE新兴技术干细胞衍生药物治疗帕金森成为一条新的探索帕金森治疗的路径。继拜耳BlueRock之后，睿健医药成为国际第二家、国内首家提交帕金森领域多能干细胞衍生药物临床申请的公司。2022年4月28日，国家药监局受理了睿健医药自主研发的帕金森管线人源多巴胺能前体细胞注射液NouvNeu001的IND申请。临床前数据显示，通过睿健医药自研的高效化学小分子诱导功能细胞再生技术，NouvNeu001 移植入体内后可高效转化为成熟多巴胺能神经元，分泌多巴胺递质，并与体内原有神经元形成神经连接，产生综合性的治疗功能，改善帕金森症状。这类前体细胞除了能够分泌多巴胺这类递质之外，还可进一步分泌多种蛋白及小核酸来改善帕金森病灶，为移植到脑部的细胞发挥作用提供良好的“土壤”环境。企业交易活动国内对帕金森病的研究对比国际略显落后，因此一些企业开始引进海外的产品和技术。2018年1月，万邦生化（母公司复星医药）与葡萄牙公司BIAL达成合作，在中国大陆独家销售代理其帕金森病治疗药物奥吡卡朋；2020年10月，日本药企Kissei Pharmaceutical宣布已与中国生物医药公司AffaMed Therapeutics就其帕金森在研新药KDT-3594达成许可协议，Affamed Therapeutics将获得在大中华区（包括中国大陆、香港、澳门和台湾地区）和东南亚六国（包括新加坡，马来西亚，泰国，印尼，越南和菲律宾）开发和商业化KDT-3594（DAs）的独家权利;2021年4月，赛神医药与礼来达合作，获得在大中华区开发和商业化针对帕金森病α-突触核蛋白靶向疗法的权利；2022年3月，上海中泽医药与美国公司 Digestome Therapeutics达成合作，获得后者DGX-001在大中华市场的独家权利。DGX-001是一种全球首创口服治疗药物，可用于治疗精神分裂症的阴性症状和认知障碍，以及帕金森病的非运动症状；2022年3月，翼思生物与德国史达德大药厂（STADA Arzneimittel AG）子公司Brtiannia Pharmaceuticals Ltd签署了一项许可协议，获得在中国大陆、香港和澳门开发和商业其皮下注射阿扑吗啡用于帕金森病的独家权利；2023年5月，畅溪制药与美国公司Acorda Therapeutics达成合作，引进后者INBRIJA（左旋多巴吸入粉雾剂）在大中华地区（中国大陆及港澳台地区）的权利。INBRIJA已在美国和欧盟获批上市，用于正在接受左旋多巴-多巴脱羧酶抑制剂治疗的成年帕金森病患者，其在关闭期（OFF episodes）的间歇性治疗；2024年1月，斯坦福大学与先声药业达成合作研究协议，将共同推动一项神经系统领域的探索性研究，为帕金森患者研发创新疗法。帕金森发现至今，目前虽有多种可以缓解症状的疗法，但还没有一种能够延缓疾病进展或治愈疾病。未来，开发这一疾病更理想的治疗方法依然是医学领域的重要目标之一。\ | /★联系我们投稿 | 发稿 | 媒体合作▶ sylvia.hua@generalbiologic.com数据库 | 咨询服务 | 资讯追踪▶ 点击左下“阅读原文”完成表单填写点击阅读原文立即订阅相关报告

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