کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8963288 | 1646615 | 2018 | 38 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
G2019S LRRK2 mutation facilitates α-synuclein neuropathology in aged mice
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کلمات کلیدی
SNCLRRK2Iba-1 - IBA-1α-synuclein - α-سینوکلینParkinson's disease - بیماری پارکینسونleucine-rich repeat kinase 2 - تکرار کیناز 2 غنی از لوسینtyrosine hydroxylase - تیروزین هیدروکسیلازDopamine - دوپامینSubstantia nigra compacta - متراکم توده سیاهionized calcium binding adaptor molecule 1 - مولکول آداپتور اتصال دهنده کلسیم یونیزه 1Microglia - میکروگلیاها
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
عصب شناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Fibrillization of α-synuclein is instrumental for the development of Parkinson's disease (PD), thus modulating this process can have profound impact on disease initiation/progression. Here, the impact of the p.G2019S mutation of leucine-rich repeat kinase 2 (LRRK2), which is most frequently associated with familial and sporadic PD, on α-synuclein pathology was investigated. G2019S knock-in mice and wild-type controls were injected with a recombinant adeno-associated viral vector serotype 2/9 (AAV2/9) overexpressing human mutant p.A53T α-synuclein (AAV2/9-hα-syn). Control animals were injected with AAV2/9 carrying green fluorescent protein. Motor behavior, transgene expression, α-syn and pSer129 α-syn load, number of nigral dopamine neurons and density of striatal dopaminergic terminals were evaluated. To investigate the effect of aging, experiments were performed in 3- and 12-month-old mice, evaluated 20 and 12â¯weeks after virus injection, respectively. hα-syn overexpression induced progressive motor deficits, loss of nigral dopaminergic neurons and striatal terminals, and appearance of proteinase K-resistant aggregates of pSer129 α-syn in both young and old mice. Although no genotype difference was observed in 3-month-old mice, degeneration of nigral dopaminergic neurons was higher in 12-month-old G2019S knock-in mice compared with age-matched wild-type controls (â55% vs â39%, respectively). Consistently, a two-fold higher load of pSer129 α-syn aggregates was found in 12-month-old G2019S knock-in mice. We conclude that G2019S LRRK2 facilitates α-synucleinopathy and degeneration of nigral dopaminergic neurons, and that aging is a major determinant of this effect.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neurobiology of Disease - Volume 120, December 2018, Pages 21-33
Journal: Neurobiology of Disease - Volume 120, December 2018, Pages 21-33
نویسندگان
Salvatore Novello, Ludovico Arcuri, Sandra Dovero, Nathalie Dutheil, Derya R. Shimshek, Erwan Bezard, Michele Morari,