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Microtubule acetylation dyshomeostasis in Parkinson’s disease

Translational Neurodegeneration 2023年第1期12卷 576-600页

作者： Padmashri Naren Khan Sabiya Samim kamatham pushpa tryphena Lalitkumar K.Vora Saurabh Srivastava Dharmendra Kumar Khatri Shashi Bala Singh Molecular and Cellular Neuroscience Lab Department of Pharmacology and ToxicologyNational Institute of Pharmaceutical Education and Research(NIPER)HyderabadTelangana 500037India School of Pharmacy Queen’s University Belfast97 Lisburn RoadBelfast BT97BLUK Department of Pharmaceutics National Institute of Pharmaceutical Education and Research(NIPER)HyderabadTelangana 500037India

The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule(MT)-mediated axonal transport *** mechanistically regulated system delivers cargos(proteins,mRNAs and organelles such as mitochondria)back and forth from the soma to the *** 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,*** 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 *** 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 *** 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 *** 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 *** enzymatic regulators of MT acetylation along with their synthetic modulators have also been briefly *** 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

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