کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
6272970 1614792 2015 14 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Changes in actin dynamics and F-actin structure both in synaptoneurosomes of LRRK2(R1441G) mutant mice and in primary human fibroblasts of LRRK2(G2019S) mutation carriers
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی علوم اعصاب (عمومی)
پیش نمایش صفحه اول مقاله
Changes in actin dynamics and F-actin structure both in synaptoneurosomes of LRRK2(R1441G) mutant mice and in primary human fibroblasts of LRRK2(G2019S) mutation carriers
چکیده انگلیسی


- The PD-linked LRRK2(R1441G) mutation destabilizes F-actin in synaptic terminals.
- LRRK2(G2019S) increases susceptibility of F-actin to Latrunculin in human fibroblasts.
- LRRK2(G2019S) increases F-actin bundling and decreases filopodial length in human fibroblasts.
- Lack of LRRK2 age-dependently alters GluN2A integration into the postsynaptic density.
- Lack of LRRK2 decreases phosphatidylserine externalization at synaptic terminals.

Converging evidence suggests that the Parkinson's disease-linked leucine-rich repeat kinase 2 (LRRK2) modulates cellular function by regulating actin dynamics. In the present study we investigate the role of LRRK2 in functional synaptic terminals of adult LRRK2-knockout and LRRK2(R1441G)-transgenic mice as well as in primary fibroblasts of LRRK2(G2019S) mutation carriers. We show that lack of LRRK2 decreases and overexpression of mutant LRRK2 age-dependently increases the effect of the actin depolymerizing agent Latrunculin A (LatA) on the synaptic cytoskeleton. Similarly, endogenous mutant LRRK2 increases sensitivity to LatA in primary fibroblasts. Under basal conditions however, these fibroblasts show an increase in F-actin bundles and a decrease in filopodial length which can be rescued by LatA treatment. Our data suggest that LRRK2 alters actin dynamics and F-actin structure both in brain neurons and skin fibroblasts. We hypothesize that increased F-actin bundling represents a compensatory mechanism to protect F-actin from the depolymerizing effect of mutant LRRK2 under basal conditions. Our data further indicate that LRRK2-dependent changes in the cytoskeleton might have functional consequences on postsynaptic NMDA receptor localization.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neuroscience - Volume 284, 22 January 2015, Pages 311-324
نویسندگان
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