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Decreased FAK activity and focal adhesion dynamics impair proper neurite formation of medium spiny neurons in Huntington's disease

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Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion in the protein huntingtin (HTT) [55]. While the final pathological consequence of HD is the neuronal cell death in the striatum region of the brain, it is still unclear how mutant HTT (mHTT) causes synaptic dysfunctions at the early stage and during the progression of HD. Here, we discovered that the basal activity of focal adhesion kinase (FAK) is severely reduced in a striatal HD cell line, a mouse model of HD, and the human post-mortem brains of HD patients. In addition, we observed with a FRET-based FAK biosensor [59] that neurotransmitter-induced FAK activation is decreased in HD striatal neurons. Total internal reflection fluorescence (TIRF) imaging revealed that the reduced FAK activity causes the impairment of focal adhesion (FA) dynamics, which further leads to the defect in filopodial dynamics causing the abnormally increased number of immature neurites in HD striatal neurons. Therefore, our results suggest that the decreased FAK and FA dynamics in HD impair the proper formation of neurites, which is crucial for normal synaptic functions [52]. We further investigated the molecular mechanism of FAK inhibition in HD and surprisingly discovered that mHTT strongly associates with phosphatidylinositol 4,5-biphosphate, altering its normal distribution at the plasma membrane, which is crucial for FAK activation [14, 60]. Therefore, our results provide a novel molecular mechanism of FAK inhibition in HD along with its pathological mechanism for synaptic dysfunctions during the progression of HD.

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Acknowledgements

This work was supported in part by National Research Foundation of Korea grant 2021R1A2C1093429, KIST Institutional grant 2E31523, and Samsung Research Funding & Incubation Center of Samsung Electronics under Project Number SRFC-TC2003-02 (J.S.). This work was also supported by NIH grant R01NS109537 (J.L.), National Research Foundation of Korea grant NRF-2020M3E5D9079742, and KIST Institutional grant 2E31505 (H.R.).

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  1. Hae Nim Lee and Seung Jae Hyeon contributed equally to this work.

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  1. Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea

    Hae Nim Lee, Seung Jae Hyeon, Heejung Kim, Kyoung Mi Sim, Yunha Kim, Jeongmin Ju, Hoon Ryu & Jihye Seong

  2. Department of Converging Science and Technology, Kyung Hee University, Seoul, 02453, Republic of Korea

    Hae Nim Lee, Heejung Kim & Jihye Seong

  3. Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea

    Jeongmin Ju & Jihye Seong

  4. Department of Neurology, Boston University Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA, 02118, USA

    Junghee Lee

  5. Department of Bioengineering, University of California, San Diego, CA, 92093, USA

    Yingxiao Wang

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JS and HR designed research; HNL, SJH, HK, KMS, YK, JJ performed experiments; JS, HR, HNL, SJH, JL, YW analyzed data; JS, HR, HNL wrote the manuscript.

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Lee, H.N., Hyeon, S.J., Kim, H. et al. Decreased FAK activity and focal adhesion dynamics impair proper neurite formation of medium spiny neurons in Huntington's disease. Acta Neuropathol 144, 521–536 (2022). https://doi.org/10.1007/s00401-022-02462-z

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