MGC4618 antibody - N-terminal region (ARP34360_P050)
- Known as:
- MGC4618 (anti-) - N-terminal region (ARP34360_P050)
- Catalog number:
- arp34360_p050
- Product Quantity:
- USD
- Category:
- -
- Supplier:
- Aviva Systems Biology
- Gene target:
- MGC4618 antibody - N-terminal region (ARP34360_P050)
Related genes to: MGC4618 antibody - N-terminal region (ARP34360_P050)
- Gene:
- TMEM175 NIH gene
- Name:
- transmembrane protein 175
- Previous symbol:
- -
- Synonyms:
- MGC4618
- Chromosome:
- 4p16.3
- Locus Type:
- gene with protein product
- Date approved:
- 2006-08-29
- Date modifiied:
- 2015-09-29
Related products to: MGC4618 antibody - N-terminal region (ARP34360_P050)
Related articles to: MGC4618 antibody - N-terminal region (ARP34360_P050)
- Microglia, the resident immune cells of the central nervous system (CNS), maintain brain homeostasis and respond to pathological insults. Microglial dysfunction has been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Impaired lysosomal function, particularly defective lysosomal acidification, leads to the accumulation of undegraded material, thereby promoting neuroinflammation and neuronal damage. - Source: PubMed
Publication date: 2026/08/03
Jaganathan RavindranVijayakumar SrilakshmiChen YinchiYe JiaxiBakthavatchalam PugazhandhiWankhar DapkuparYang ChuanbinIyaswamy AshokLi Min - The transmembrane protein 175 (TMEM175) is a high-risk gene for Parkinson's disease (PD) and encodes an ion channel in lysosomes. Many PD-associated variants in TMEM175 lead to the loss of ion channel function. In this study, we identified the PD-associated TMEM175-L156P variant is a missense mutation with trafficking deficiency. Using imaging, biochemical, and whole-endolysosomal electrophysiological approaches, we identified that L156P abolished the lysosomal expression of TMEM175; instead, it accumulates in the endoplasmic reticulum (ER). The cytosolic segment of the fourth transmembrane helix (TM4-1), where the L156 resides, determined the lysosomal localization of TMEM175. Having understood the structural basis, we evaluated wild-type (WT) TMEM175 and pharmacological chaperones previously used in cystic fibrosis treatment. We elucidated that WT partially rescued the aberrant expression of L156P. Moreover, the chaperones substantially reduced the ER-retained L156P and facilitated its trafficking to lysosomes. We further screened and identified a bifunctional chemical molecule that both corrected the trafficking defects and potentiated the ion channel function of L156P. Notably, the chemical-restored L156P is functional, as it relieves the lysosomal over-acidification. Conclusively, we establish the relationship between aberrant trafficking and pathogenesis in PD, demonstrating the potential of utilizing "chaperone plus agonist" bifunctional chemical molecules as personalized treatment for PD. - Source: PubMed
Publication date: 2026/07/31
Luo TingHe YuLi ShuyaoGuan HaoyuCui RuiliShi YuJiang ZhongwenWang SiyuLi XuanLi JiyuanHu MeiZhou YupengTang BeishaZhang YanyanGao ZhaobingZhou YuLiu ZhenhuaLi Ping - Alzheimer's disease (AD), Parkinson's disease (PD) and Lewy body dementia (LBD) overlap clinically, pathologically and genetically, complicating interpretation of cross-disorder genome-wide association study (GWAS) signals. - Source: PubMed
Publication date: 2026/07/02
Zhang YingZhang ZhishuaiQiu ShizhengHu Yang - TMEM175 is a lysosomal cation channel essential for maintaining lysosomal pH and function. Dysregulation of TMEM175 has been implicated in Parkinson's disease, highlighting the need for small-molecule modulators to probe its physiological and therapeutic roles. We previously screened an FDA-approved compound library for TMEM175 modulators using a plasma membrane overexpression system that enables functional analysis of channel activity. Here, we report the pharmacological characterization of the most potent hit, candesartan cilexetil. In fluorescence-based thallium flux, automated patch-clamp, and manual patch-clamp assays, candesartan cilexetil robustly activates TMEM175 with efficacy comparable with the reference activator DCPIB, whereas its hydrolyzed metabolite candesartan is inactive. Candesartan cilexetil is active only when applied to the extracellular (lysosome lumen-equivalent) side of the channel and is inactive from the cytosolic-facing side. To determine whether activation requires the intact prodrug, we generated analogs that modify or eliminate the cilexetil and ester functionalities. Structure-activity studies show that selected modifications of the cilexetil moiety reduce potency while preserving maximal efficacy, whereas more extensive modification markedly reduces intrinsic activity, indicating that it is an essential pharmacophoric element rather than a simple membrane-permeating handle. Manual patch-clamp wash-off experiments further demonstrate direct, reversible activation without requiring membrane permeation or hydrolysis. Unexpectedly, the nonhydrolyzable analog VU0982645 exhibits minimal intrinsic activity yet produces robust synergistic activation with DCPIB. Together, these findings establish the cilexetil handle as a key pharmacophoric element and support synergistic modulation as a tractable mechanism for activating TMEM175. We introduce a new therapeutic paradigm for TMEM175 targeting by demonstrating that synergistic agonist pairs can drive robust channel activation. Beyond identifying candesartan cilexetil as a moderately potent activator with a previously unrecognized pharmacophoric cilexetil moiety, we show that a minimally active analog can dramatically potentiate activation in combination with DCPIB. This synergistic strategy establishes TMEM175 as a tractable therapeutic target and reveals coagonism as a powerful mechanism to modulate lysosomal ion channels. - Source: PubMed
Publication date: 2026/07/02
Li KangjunLe Samantha DSatpute Janve VaishaliLazarenko Roman MRomaine Ian MKim KwanghoSulikowski Gary AWaterson Alex GDenton Jerod S - Gut microbiota dysbiosis contributes to Parkinson's disease (PD) pathology by altering dopamine metabolism in the gut-brain axis. Although probiotics and other functional strains have been proposed as microbiome-based interventions, few naturally occurring gut microbes show therapeutic potential for PD. Here, we isolated Enterococcus hirae QT4713 (QT4713) from the hypoxic, low-pressure Qinghai-Tibet Plateau (4713 m altitude). Whole-genome sequencing revealed that QT4713 harbors a tyrosine decarboxylase gene (TyrDc), enabling conversion of L-tyrosine to dopamine in vitro. In mice, QT4713 enhanced antioxidant enzyme activity, reduced inflammatory mediators, reshaped gut microbial composition, and promoted short-chain fatty acid production. Metabolomic analyses indicated activation of L-tyrosine metabolism, with increased L-DOPA and dopamine levels in the colon and feces, accompanied by improved motor performance. In an MPTP-induced PD mouse model, QT4713 alleviated motor and gastrointestinal dysfunction, reduced oxidative and inflammatory damage, and attenuated dopaminergic neuron loss. QT4713 also increased dopamine and tyrosine levels in the striatum. Extending beyond an acute toxin model, QT4713 partially rescued PD-like phenotypes in TMEM175 knockout mice, preserving tyrosine hydroxylase-positive neurons in the substantia nigra. Together, these findings suggest that QT4713 can mitigate gastrointestinal disturbances and other PD-related deficits, consistent with combined effects on catecholamine-related metabolism and gut microbiota remodeling. - Source: PubMed
Publication date: 2026/05/19
Zhao TingtingLi BinLiu YimingZhang JiaruiFan XueniAo MingyangNiu YuanlinLi DiantongHe JinSun DongWu HuiTang TuoxianLiu ZhenjiangHuang Xiaodan