Ask about this productRelated genes to: SNCA protein
- Gene:
- SNCA NIH gene
- Name:
- synuclein alpha
- Previous symbol:
- PARK1, PARK4
- Synonyms:
- NACP, PD1
- Chromosome:
- 4q22.1
- Locus Type:
- gene with protein product
- Date approved:
- 1995-01-24
- Date modifiied:
- 2018-04-18
Related products to: SNCA protein
Related articles to: SNCA protein
- Pathological accumulation of toxic SNCA species and loss of E3-ligase function of PRKN are two key features observed in Parkinson disease (PD). Here, we established the contribution of an E3-ligase-independent transcriptional function of PRKN in SNCA regulation. PRKN depletion decreased and (glucosylceramidase beta 1) mRNA levels and reduced CMA-driven degradation of SNCA, thereby triggering the accumulation of its phosphorylated aggregation-prone toxic species. We established that PRKN controls the CMA player LAMP2A but not HSPA8/HSC70 in isolated lysosomal fractions prepared from human neuronal and mouse fibroblastic cells. Further, we showed that PRKN-associated regulation of LAMP2 is isoform specific. We showed that PRKN-mediated control of SNCA, GBA1 and LAMP2A occurs and is impaired in the paraquat-treated PD mice model. We showed that the levels of phosphorylated SNCA and PRKN are correlated in sporadic PD human brain samples and that fibroblasts of patients carrying pathogenic mutations exhibit impaired CMA activity. Our study decrypts a new molecular mechanism linking three PD major therapeutic targets. It enriches the portfolio of transcriptional targets of PRKN and establishes PRKN as a novel CMA regulator. Further, it shows that PRKN controls both direct and indirect (GBA1-dependent) transcriptional regulation of . This novel molecular cascade opens potential new avenues in PD treatment. - Source: PubMed
Publication date: 2026/05/04
Ramos Dos Santos LígiaDuplan EricDebord JulianeFremont GwendolineMinniti JulienLauritzen IngerMutez EugenieLeghay ColineChartier-Harlin Marie ChristineChecler FrédéricAlves da Costa Cristine - Parkinson's disease (PD) is clinically heterogeneous, yet the genetic architecture underlying this heterogeneity remains incompletely understood. We examined the genetic correlates of four complementary PD subtyping frameworks: the clinical motor subtype (tremor-dominant [TD] vs. postural instability/gait difficulty [PIGD]), alpha-synuclein seed amplification assay status (SAA+ vs. SAA-), the pathological subtype (brain-first vs. body-first, based on the presence of REM sleep behavior disorder), and the data-driven subtype (diffuse malignant [DM] vs. mild-motor predominant [MMP] vs. intermediate [IM]). We analyzed 1390 PD patients from the Parkinson's Progression Markers Initiative (PPMI) with genotypes available for seven PD-associated genes (, , , , , , ), including specific variant resolutions (, ; , severe variants; ), and (ε2/ε3/ε4 alleles). Genetic variant frequencies were compared across subtypes using chi-square or Fisher's exact tests with the Benjamini-Hochberg false discovery rate (FDR) correction. Effect sizes were quantified using Cramér's V. multivariable logistic regression estimated adjusted odds ratios with Wald-based 95% confidence intervals. Among genotyped PD patients, carriers constituted 13.7% (190/1390; 170 , 18 ), 8.6% (119/1390; 96 , 23 severe), and 2.0% (28/1390; all ). ε4 carriers comprised 23.4% (323/1380). SAA-negative patients were markedly enriched for variants (37.1% vs. 10.2%, = 3.7 × 10, q < 0.001, V = 0.25), specifically (28.5% vs. 9.6%, = 4.9 × 10, q < 0.001) and (7.9% vs. 0.5%, = 2.7 × 10, q < 0.001). Body-first PD was enriched for carriers (12.3% vs. 6.7%, = 0.004, q = 0.021) and had less carriers (7.9% vs. 15.0%, = 0.002, q = 0.013). The DM subtype had the highest frequency (14.0% vs. MMP 5.9%, < 0.001, q = 0.003). After FDR correction, 10 out of 48 univariate tests remained significant. Clinical subtypes (TD vs. PIGD) showed only nominal differences that did not survive FDR correction. The genotype did not differ across any framework. PD subtypes defined by alpha-synuclein pathology (SAA), pathological onset pattern (brain-first/body-first), and data-driven classification (DM/MMP/IM) show distinct genetic profiles that survive multiple comparison correction. variants strongly associate with SAA negativity (V = 0.25); variants associate with the severe body-first onset and the diffuse malignant subtype. - Source: PubMed
Publication date: 2026/04/13
Negida AhmedAbouelmagd Moaz ElsayedHamed Belal MohamedHawas YousefDziri AyaNegida YasminBerman Brian DBarrett Matthew J - : Pathogenic mutations in leucine-rich repeat protein kinase-2 (), particularly G2019S, constitute the most common cause of autosomal dominant PD. : Mouse models encoding human mutant alpha-synuclein () and G2019S were treated with a brain-penetrant kinase inhibitor (BK40196). Behavior, nigrostriatal and mesolimbic dopamine (DA) pathways were examined. : Mice harboring do not show age-dependent motor symptoms, but mice encoding A53T display motor deficits, while both strains exhibit anxiety-like behavior and BK40196 improves motor and behavioral defects. BK40196, a multi-kinase inhibitor of Abelson (Abl), Discoidin domain receptor (DDR)-1, c-KIT and FYN, alters microglial morphology and alpha-synuclein levels in A53T mice and improves DA neurotransmission, primarily via the nigrostriatal system. BK40196 inhibits brain LRRK2 G2019S (IC of 89nM) and does not affect phosphorylated or total peripheral LRRK2 levels (lungs, kidneys, liver, etc.). G2019S mice treated with BK40196 exhibit distinct increases in DA in mesolimbic neurons such as the nucleus accumbens (NAcc), suggesting differential mechanisms of DA neurotransmission in mutant alpha-synuclein and models of PD. : G2019S may primarily involve mesolimbic pathways leading to nonmotor symptoms independent of the motor and behavioral manifestations associated with alpha-synuclein via the nigrostriatal system. BK40196 may provide a comprehensive and synergistic therapeutic approach that addresses multiple mechanisms to reduce the pathologies related to G2019S and/or in PD. The multiple pathologies of PD necessitate a holistic approach that simultaneously targets inflammation and autophagy and LRRK2 inhibition. - Source: PubMed
Publication date: 2026/04/18
Liu XiaoguangBaxely SeanHebron Michaeline LMoussa Charbel - Neonatal bacterial sepsis (NBS) remains a major global burden. Although immune dysfunction is central to its pathogenesis, the causal contribution of specific immune cell phenotypes and their upstream genetic regulation is unclear. This study aimed to test whether genetically predicted gene expression influences NBS risk through immune cell traits using an integrative two-step Mendelian randomization (MR) mediation framework. We combined eQTLGen whole-blood expression quantitative trait loci (n ≈ 30,000), genome-wide association study of 731 immune traits (Sardinian cohort, n ≈ 3757), and FinnGen R12 NBS summary statistics (P16_BACTERIAL_SEPSIS_NEWBO; 203 cases, 499,933 controls). Instruments met genome-wide significance, stringent linkage disequilibrium clumping, and F-statistic >10. Primary analyses used inverse-variance weighted MR, with MR-Egger and weighted median as sensitivity analyses. Mediation was estimated as the product of effects. Colocalization (coloc; summary-data-based Mendelian randomization-heterogeneity in dependent instruments) was used to evaluate shared causal variants. Heterogeneity (Cochran Q), MR-Egger intercepts, leave-one-out, and reverse MR were performed. We identified 147 gene expressions and 23 immune traits associated with NBS after false discovery rate correction. Two-step MR yielded multiple gene-immune-NBS mediation chains, with CD28-related T-cell phenotypes consistently prominent. The TRPM4 → CD28 on double-negative T cells → NBS pathway showed the largest mediation proportion (~40.54%) and remained directionally consistent across sensitivity tests. Several colocalized signals (e.g., DBF4B, SNCA, SYCE1L) supported shared variants with immune traits; however, not all corresponding mediation paths passed heterogeneity/sensitivity checks, and are therefore interpreted as suggestive rather than definitive. Associations involving CD64 on monocyte subsets were not robust across sensitivity analyses and were not retained as primary findings. Reverse MR did not indicate feedback from NBS liability to the immune traits prioritized in forward analyses. Genetically informed immune phenotypes (particularly CD28-related T-cell features and the broader CD8bright/regulatory T cell axis) appear to partly mediate the effect of gene expression on NBS susceptibility. Colocalized mediation signals provide supportive, hypothesis-generating evidence but require cautious interpretation given sensitivity/heterogeneity findings. These results motivate neonatal-specific validation and functional studies to refine mechanistic targets for risk stratification. - Source: PubMed
Liang JingWei RongYi WeiChen JunchangLi DongxiaoXiao LinLai QiuruFang QiutingLü JibaoWei YingcaiYuan JiaquanGan Junhong - Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta and pathological accumulation of α-synuclein in Lewy bodies. In this process, a set of non-coding RNAs including miRNAs, lncRNAs, and circRNAs form key regulatory layers in the pathogenesis of the disease and directly affect α-synuclein homeostasis, mitochondrial function, oxidative stress, neuroinflammation, autophagy, and proteostasis. Dysregulation of miRNAs targets neurosensitive pathways; miR-7 and miR-153 inhibit SNCA translation, miR-27a/b and miR-103a-3p regulate the PINK1/Parkin axis in mitophagy, and miR-155, together with miR-135b, modulate the regulation of the NF-κB/NLRP3 dependent inflammasome. On a broader level, lncRNAs with destructive roles such as NEAT1, HOTAIR, MALAT1, SNHG1, UCA1 and GAS5 increase α-synuclein accumulation and impair autophagy through ceRNA and chromatin remodeling mechanisms. On the other hand, circRNAs with their stable circular structure alter posttranslational regulation through miRNA sponging; such that circSNCA, CDR1as and circSLC8A1 enhance α-synuclein load, impair mitophagy and exacerbate oxidative stress, while circDLGAP4 has a neuroprotective function. Data from single-cell sequencing and multi-omics reveal cell-specific patterns of ncRNA dysregulation in microglia, astrocytes and dopaminergic neurons, highlighting their importance in early diagnosis, molecular stratification of patients and development of targeted therapies. - Source: PubMed
Publication date: 2026/04/30
Tang PatrickJing ZiluoTong ZhengliangPeng XiangyuTong JenniferPeng Yizi