Lee, Hae Nim Hyeon, Seung Jae Kim, Heejung Sim, Kyoung Mi Kim, Yunha Ju, Jeongmin Lee, Junghee Wang, Yingxiao Ryu, Hoon Seong, Jihye 2024-01-19T11:30:17Z 2024-01-19T11:30:17Z 2022-08-04 2022-09 0001-6322 https://pubs.kist.re.kr/handle/201004/114730 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. English Springer Verlag Decreased FAK activity and focal adhesion dynamics impair proper neurite formation of medium spiny neurons in Huntington's disease Article 10.1007/s00401-022-02462-z 1 Acta Neuropathologica, v.144, pp.521 - 536 Acta Neuropathologica 144 521 536 N scie scopus 000829653200001 Clinical Neurology Neurosciences Pathology Neurosciences & Neurology Pathology Article; Early Access MOLECULAR-MECHANISMS SYNAPTIC PLASTICITY DYSTROPHIC NEURITES EPHB RECEPTORS KINASE FILOPODIA MIGRATION PROTEIN PHOSPHOLIPIDS MUTANT HUNTINGTIN Focal adhesion kinase (FAK) Huntingtin Focal adhesion dynamics Neurites PtdIns(4 5)P-2 Huntington&apos s disease