Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease.
Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease.
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DOI：
10.3389/fneur.2022.971252
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发表时间：
2022
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
--
作者：
GBA1和LRRK2基因变异是与帕金森病(PD)相关的最常见的遗传风险因素。这两个基因都与溶酶体和自噬途径有关，GBA1基因编码溶酶体酶，葡萄糖脑苷酶(GCase)和LRRK2基因编码富含亮氨酸的重复蛋白激酶2酶。与散发性帕金森病相比，GBA1相关帕金森病的特点是发病年龄更早，非运动症状更严重。根据疾病的临床表现，GBA1基因的突变可分为重度、轻度和高风险变异。对于GBA1变体，已经提出了功能丧失和功能获得的假说，与每个变体相关的功能后果通常与突变的严重程度有关。另一方面，LRRK2相关的PD类似于散发性PD，但具有更良性的病程。LRRK2基因的突变发生在几个结构域中，并影响GTP酶的磷酸化。生化研究表明GBA1和LRRK2通路可能趋同，与GBA1相关的PD相比，双突变携带者表现出更温和的表型。这篇综述比较了GBA1和LRRK2相关的PD，并强调了基于单个变种的生化结果，GBA1和LRRK2可能分别与基因型和表型相关。
Variants in the GBA1 and LRRK2 genes are the most common genetic risk factors associated with Parkinson disease (PD). Both genes are associated with lysosomal and autophagic pathways, with the GBA1 gene encoding for the lysosomal enzyme, glucocerebrosidase (GCase) and the LRRK2 gene encoding for the leucine-rich repeat kinase 2 enzyme. GBA1-associated PD is characterized by earlier age at onset and more severe non-motor symptoms compared to sporadic PD. Mutations in the GBA1 gene can be stratified into severe, mild and risk variants depending on the clinical presentation of disease. Both a loss- and gain- of function hypothesis has been proposed for GBA1 variants and the functional consequences associated with each variant is often linked to mutation severity. On the other hand, LRRK2-associated PD is similar to sporadic PD, but with a more benign disease course. Mutations in the LRRK2 gene occur in several structural domains and affect phosphorylation of GTPases. Biochemical studies suggest a possible convergence of GBA1 and LRRK2 pathways, with double mutant carriers showing a milder phenotype compared to GBA1-associated PD. This review compares GBA1 and LRRK2-associated PD, and highlights possible genotype-phenotype associations for GBA1 and LRRK2 separately, based on biochemical consequences of single variants.
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DOI：
10.3233/jpd-179001
发表时间：
2017
期刊：
Journal of Parkinson's disease
影响因子：
--
作者：
Braak H;Del Tredici K
通讯作者：
Del Tredici K
影响因子：
8.6
作者：
Alcalay, Roy N.;Mirelman, Anat;Saunders-Pullman, Rachel;Tang, Ming-X;Mejia Santana, Helen;Raymond, Deborah;Roos, Ernest;Orbe-Reilly, Martha;Gurevich, Tanya;Bar Shira, Anat;Weisz, Mali Gana;Yasinovsky, Kira;Zalis, Maayan;Thaler, Avner;Deik, Andres;Barrett, Matthew James;Cabassa, Jose;Groves, Mark;Hunt, Ann L.;Lubarr, Naomi;San Luciano, Marta;Miravite, Joan;Palmese, Christina;Sachdev, Rivka;Sarva, Harini;Severt, Lawrence;Shanker, Vicki;Swan, Matthew Carrington;Soto-Valencia, Jeannie;Johannes, Brooke;Ortega, Robert;Fahn, Stanley;Cote, Lucien;Waters, Cheryl;Mazzoni, Pietro;Ford, Blair;Louis, Elan;Levy, Oren;Rosado, Llency;Ruiz, Diana;Dorovski, Tsvyatko;Pauciulo, Michael;Nichols, William;Orr-Urtreger, Avi;Ozelius, Laurie;Clark, Lorraine;Giladi, Nir;Bressman, Susan;Marder, Karen S.
通讯作者：
Marder, Karen S.
影响因子：
5.6
作者：
Cerri S;Ghezzi C;Ongari G;Croce S;Avenali M;Zangaglia R;Di Monte DA;Valente EM;Blandini F
通讯作者：
Blandini F
影响因子：
9.9
作者：
Clark, L. N.;Ross, B. M.;Marder, K.
通讯作者：
Marder, K.
影响因子：
2.4
作者：
Biskup S;Moore DJ;Rea A;Lorenz-Deperieux B;Coombes CE;Dawson VL;Dawson TM;West AB
通讯作者：
West AB