Zhang Hanwen, Kargilis Daniel, Tropea Thomas, Robinson John, Shen Junchao, Brody Eliza M, Brinkmalm Ann, Sjödin Simon, Berndt Adama J, Carceles-Cordon Marc, Suh EunRan, Van Deerlin Vivianna M, Blennow Kaj, Weintraub Daniel, Lee Edward B, Zetterberg Henrik, Chen-Plotkin Alice S
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Ann Clin Transl Neurol. 2025 May;12(5):925-937. doi: 10.1002/acn3.52286. Epub 2025 Mar 7.
Several genetic loci known to confer risk for Parkinson's disease (PD) function in lysosomal pathways. We systematically screened common variants linked to PD risk by genome-wide association studies (GWAS) for impact on cerebrospinal fluid (CSF) proteins reflecting lysosomal function.
Starting with 525 candidate gene-single nucleotide polymorphism (SNPs) pairs nominated by Mendelian randomization from published PD GWAS, we filtered SNPs for downstream evaluation, based on strength of association with PD and impact on brain gene expression. We genotyped top SNPs in 173 PD participants, adding three SNPs capturing variation at the TMEM106B, CTSB, and RAB29 loci, encoding genes with known lysosomal function. In the same 173 individuals, we measured 15 CSF proteins (nine lysosomal proteins and six other proteins implicated in neurodegeneration) by parallel reaction monitoring mass spectrometry. We tested SNPs for association with lysosomal proteins. For our top SNP associating with multiple lysosomal proteins, we characterized expression of its target gene CAMLG in human brain tissue.
Sixteen SNPs emerged from our analysis of GWAS-nominated loci. Genotypes at rs12657663 (CAMLG) associated with CSF levels of multiple lysosomal markers (cathepsin F, cathepsin L, hexosaminidase B, and tripeptidyl peptidase I) and genotypes at rs7910668 (ITGA8) with CSF levels of cathepsin B. The protein encoded by CAMLG, calcium modulating ligand (CAML), is highly expressed in neurons of multiple human brain regions, with higher expression in Lewy body disease cases.
Systematic analysis of PD risk loci nominates CAMLG as a neuronally expressed risk gene with effects on lysosomes.
已知几个与帕金森病（PD）风险相关的基因位点在溶酶体途径中发挥作用。我们通过全基因组关联研究（GWAS）系统筛选与PD风险相关的常见变异，以评估其对反映溶酶体功能的脑脊液（CSF）蛋白质的影响。
从已发表的PD GWAS中通过孟德尔随机化提名的525个候选基因-单核苷酸多态性（SNP）对开始，我们根据与PD的关联强度和对脑基因表达的影响筛选SNP进行下游评估。我们对173名PD参与者中的顶级SNP进行基因分型，添加了三个捕获TMEM106B、CTSB和RAB29基因座变异的SNP，这些基因座编码具有已知溶酶体功能的基因。在相同的173名个体中，我们通过平行反应监测质谱法测量了15种CSF蛋白质（9种溶酶体蛋白质和6种其他与神经退行性变有关的蛋白质）。我们测试SNP与溶酶体蛋白质的关联。对于与多种溶酶体蛋白质相关的顶级SNP，我们表征了其靶基因CAMLG在人脑组织中的表达。
我们对GWAS提名位点的分析产生了16个SNP。rs12657663（CAMLG）的基因型与多种溶酶体标志物（组织蛋白酶F、组织蛋白酶L、己糖胺酶B和三肽基肽酶I）的CSF水平相关，rs7910668（ITGA8）的基因型与组织蛋白酶B的CSF水平相关。CAMLG编码的蛋白质钙调节配体（CAML）在多个人脑区域的神经元中高度表达，在路易体病病例中表达更高。
对PD风险位点的系统分析将CAMLG确定为一个在神经元中表达且对溶酶体有影响的风险基因。
