The functional specificity of tubulin isotypes has been demonstrated by various neurological diseases caused by an increasing number of mutations in tubulin isotypes.TUBA8 is specifically localized in cerebellar Purki...The functional specificity of tubulin isotypes has been demonstrated by various neurological diseases caused by an increasing number of mutations in tubulin isotypes.TUBA8 is specifically localized in cerebellar Purkinje cells,which exhibitthe most elaborate dendritic trees in the central nervous system.However,the role and related molecular mechanism of TUBA8 in regulating neuronal dendritic morphology remain poorly understood.Here,we report that TUBA8 is required for neuronal dendrite development.As the most divergent member inα-tubulin isotypes,the expression of TUBA8 in Purkinje cells starts at P0,plateaus at P10,and persists into adulthood.Loss of TUBA8 in Purkinje cells induces global dendritic height defects in multiple lobules during development and aging.Meanwhile,TUBA8 deficiency causes age-dependent decreased locomotor activity and anxiety-like behavior.In contrast to TUBA8,TUBA4A,another tubulin isotype highly expressed in Purkinje cells,is not required for dendrite development.Furthermore,the 40th alanine,which differs with any otherα-tubulin isotype and cannot be modified by acetylation,methylation,or lactylation,mediates the promoting effect of TUBA8 in neuronal dendrite development.This study reveals a specific role of TUBA8 in regulating neuronal dendritic morphology and highlights the importance of the 40th amino acid in implementing functions ofα-tubulin isotypes.展开更多
基金supported by grants from the National Natural Science Foundation of China(31991194)CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-082).
文摘The functional specificity of tubulin isotypes has been demonstrated by various neurological diseases caused by an increasing number of mutations in tubulin isotypes.TUBA8 is specifically localized in cerebellar Purkinje cells,which exhibitthe most elaborate dendritic trees in the central nervous system.However,the role and related molecular mechanism of TUBA8 in regulating neuronal dendritic morphology remain poorly understood.Here,we report that TUBA8 is required for neuronal dendrite development.As the most divergent member inα-tubulin isotypes,the expression of TUBA8 in Purkinje cells starts at P0,plateaus at P10,and persists into adulthood.Loss of TUBA8 in Purkinje cells induces global dendritic height defects in multiple lobules during development and aging.Meanwhile,TUBA8 deficiency causes age-dependent decreased locomotor activity and anxiety-like behavior.In contrast to TUBA8,TUBA4A,another tubulin isotype highly expressed in Purkinje cells,is not required for dendrite development.Furthermore,the 40th alanine,which differs with any otherα-tubulin isotype and cannot be modified by acetylation,methylation,or lactylation,mediates the promoting effect of TUBA8 in neuronal dendrite development.This study reveals a specific role of TUBA8 in regulating neuronal dendritic morphology and highlights the importance of the 40th amino acid in implementing functions ofα-tubulin isotypes.
