Microtubule acetylation dyshomeostasis in Parkinson’s disease  

作　　者：Padmashri Naren Khan Sabiya Samim Kamatham Pushpa Tryphena Lalitkumar K.Vora Saurabh Srivastava Dharmendra Kumar Khatri Shashi Bala Singh 

机构地区：[1]Molecular and Cellular Neuroscience Lab,Department of Pharmacology and Toxicology,National Institute of Pharmaceutical Education and Research(NIPER),Hyderabad,Telangana 500037,India [2]School of Pharmacy,Queen’s University Belfast,97 Lisburn Road,Belfast BT97BL,UK [3]Department of Pharmaceutics,National Institute of Pharmaceutical Education and Research(NIPER),Hyderabad,Telangana 500037,India

出　　处：《Translational Neurodegeneration》2023年第1期576-600,共25页转化神经变性病（英文）

摘　　要：The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule(MT)-mediated axonal transport system.This mechanistically regulated system delivers cargos(proteins,mRNAs and organelles such as mitochondria)back and forth from the soma to the synapse.Motor proteins like kinesins and dynein mechanistically regulate polarized anterograde(from the soma to the synapse)and retrograde(from the synapse to the soma)commute of the cargos,respectively.Proficient axonal transport of such cargos is achieved by altering the microtubule stability via post-translational modifications(PTMs)ofα-andβ-tubulin heterodimers,core components constructing the MTs.Occurring within the lumen of MTs,K40 acetylation ofα-tubulin viaα-tubulin acetyl transferase and its subsequent deacetylation by HDAC6 and SIRT2 are widely scrutinized PTMs that make the MTs highly flexible,which in turn promotes their lifespan.The movement of various motor proteins,including kinesin-1(responsible for axonal mitochondrial commute),is enhanced by this PTM,and dyshomeostasis of neuronal MT acetylation has been observed in a variety of neurodegenerative conditions,including Alzheimer’s disease and Parkinson’s disease(PD).PD is the second most common neurodegenerative condition and is closely associated with impaired MT dynamics and deregulated tubulin acetylation levels.Although the relationship between status of MT acetylation and progression of PD pathogenesis has become a chicken-and-egg question,our review aims to provide insights into the MT-mediated axonal commute of mitochondria and dyshomeostasis of MT acetylation in PD.The enzymatic regulators of MT acetylation along with their synthetic modulators have also been briefly explored.Moving towards a tubulin-based therapy that enhances MT acetylation could serve as a disease-modifying treatment in neurological conditions that lack it.

关 键 词：Parkinson’s disease Microtubule acetylation TUBULIN PTMS MITOCHONDRIA Axonal transport HDAC6 SIRT2 inhibitors 

分 类 号：R742.5[医药卫生—神经病学与精神病学]