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Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein.
Neuron 2009; 64(6):807-27N

Abstract

Mutations in alpha-synuclein and Leucine-rich repeat kinase 2 (LRRK2) are linked to autosomal dominant forms of Parkinson's disease (PD). However, little is known about any potential pathophysiological interplay between these two PD-related genes. Here we show in transgenic mice that although overexpression of LRRK2 alone did not cause neurodegeneration, the presence of excess LRRK2 greatly accelerated the progression of neuropathological abnormalities developed in PD-related A53T alpha-synuclein transgenic mice. Moreover, we found that LRRK2 promoted the abnormal aggregation and somatic accumulation of alpha-synuclein in A53T mice, which likely resulted from the impairment of microtubule dynamics, Golgi organization, and the ubiquitin-proteasome pathway. Conversely, genetic ablation of LRRK2 preserved the Golgi structure and suppressed the aggregation and somatic accumulation of alpha-synuclein, and thereby delayed the progression of neuropathology in A53T mice. These findings demonstrate that overexpression of LRRK2 enhances alpha-synuclein-mediated cytotoxicity and suggest inhibition of LRRK2 expression as a potential therapeutic option for ameliorating alpha-synuclein-induced neurodegeneration.

Authors+Show Affiliations

Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20064389

Citation

Lin, Xian, et al. "Leucine-rich Repeat Kinase 2 Regulates the Progression of Neuropathology Induced By Parkinson's-disease-related Mutant Alpha-synuclein." Neuron, vol. 64, no. 6, 2009, pp. 807-27.
Lin X, Parisiadou L, Gu XL, et al. Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron. 2009;64(6):807-27.
Lin, X., Parisiadou, L., Gu, X. L., Wang, L., Shim, H., Sun, L., ... Cai, H. (2009). Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron, 64(6), pp. 807-27. doi:10.1016/j.neuron.2009.11.006.
Lin X, et al. Leucine-rich Repeat Kinase 2 Regulates the Progression of Neuropathology Induced By Parkinson's-disease-related Mutant Alpha-synuclein. Neuron. 2009 Dec 24;64(6):807-27. PubMed PMID: 20064389.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. AU - Lin,Xian, AU - Parisiadou,Loukia, AU - Gu,Xing-Long, AU - Wang,Lizhen, AU - Shim,Hoon, AU - Sun,Lixin, AU - Xie,Chengsong, AU - Long,Cai-Xia, AU - Yang,Wan-Jou, AU - Ding,Jinhui, AU - Chen,Zsu Zsu, AU - Gallant,Paul E, AU - Tao-Cheng,Jung-Hwa, AU - Rudow,Gay, AU - Troncoso,Juan C, AU - Liu,Zhihua, AU - Li,Zheng, AU - Cai,Huaibin, PY - 2009/11/03/accepted PY - 2010/1/13/entrez PY - 2010/1/13/pubmed PY - 2010/2/25/medline SP - 807 EP - 27 JF - Neuron JO - Neuron VL - 64 IS - 6 N2 - Mutations in alpha-synuclein and Leucine-rich repeat kinase 2 (LRRK2) are linked to autosomal dominant forms of Parkinson's disease (PD). However, little is known about any potential pathophysiological interplay between these two PD-related genes. Here we show in transgenic mice that although overexpression of LRRK2 alone did not cause neurodegeneration, the presence of excess LRRK2 greatly accelerated the progression of neuropathological abnormalities developed in PD-related A53T alpha-synuclein transgenic mice. Moreover, we found that LRRK2 promoted the abnormal aggregation and somatic accumulation of alpha-synuclein in A53T mice, which likely resulted from the impairment of microtubule dynamics, Golgi organization, and the ubiquitin-proteasome pathway. Conversely, genetic ablation of LRRK2 preserved the Golgi structure and suppressed the aggregation and somatic accumulation of alpha-synuclein, and thereby delayed the progression of neuropathology in A53T mice. These findings demonstrate that overexpression of LRRK2 enhances alpha-synuclein-mediated cytotoxicity and suggest inhibition of LRRK2 expression as a potential therapeutic option for ameliorating alpha-synuclein-induced neurodegeneration. SN - 1097-4199 UR - https://www.unboundmedicine.com/medline/citation/20064389/Leucine_rich_repeat_kinase_2_regulates_the_progression_of_neuropathology_induced_by_Parkinson's_disease_related_mutant_alpha_synuclein_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0896-6273(09)00889-7 DB - PRIME DP - Unbound Medicine ER -