Neurons rely on the long-range trafficking of synaptic components to form and maintain complex neural networks that encode human experience. With a single neuron capable forming thousands distinct en passant synapses along its axon, spatially precise delivery necessary is paramount. How these are patterned, as well how efficient regulated, remains largely unknown. Here, we reveal novel role for microtubule (MT)-severing enzyme spastin in locally enhancing MT polymerization influence...

Microtubules are dynamic cytoskeletal polymers that mediate numerous, essential functions such as axon and dendrite growth neuron migration throughout brain development. In recent years, sequencing has revealed dominant mutations disrupt the tubulin protein building blocks of microtubules. These lead to a spectrum devastating malformations, complex neurological physical phenotypes, even fatality. The most common gene mutated is α-tubulin TUBA1A, which prevalent expressed in post-mitotic...

Gain-of-function mutations in the LRRK2 gene cause Parkinson’s disease (PD), characterized by debilitating motor and non-motor symptoms. Increased phosphorylation of a subset RAB GTPases is implicated PD pathogenesis. We find that increased RAB3A, cardinal synaptic vesicle precursor (SVP) protein, disrupts anterograde axonal transport SVPs iPSC-derived human neurons (iNeurons) expressing hyperactive LRRK2-p.R1441H. Knockout opposing protein phosphatase 1H (PPM1H) iNeurons phenocopies this...

Abstract The microtubule cytoskeleton supports diverse cellular morphogenesis and migration processes during brain development. Mutations in tubulin genes are associated with severe human malformations known as ‘tubulinopathies’; however, it is not understood how molecular-level changes subunits lead to malformations. In this study, we demonstrate that missense mutations affecting arginine at position 402 (R402) of TUBA1A α-tubulin selectively impair dynein motor activity severely dominantly...

The neuronal cytoskeleton performs incredible feats during nervous system development. Extension of processes, migration, and synapse formation rely on the proper regulation microtubules. Mutations that disrupt primary α-tubulin expressed brain development, TUBA1A, are associated with a spectrum human malformations. One model posits TUBA1A mutations lead to reduction in tubulin subunits available for microtubule polymerization, which represents haploinsufficiency mechanism. We propose an...

Developing neurons undergo dramatic morphological changes to appropriately migrate and extend axons make synaptic connections. The microtubule cytoskeleton, made of α/β-tubulin dimers, drives neurite outgrowth, promotes neuronal growth cone responses, facilitates intracellular transport critical cargoes during neurodevelopment. TUBA1A constitutes the majority α-tubulin in developing brain mutations humans cause severe malformations accompanied by varying neurological defects, collectively...

Heterozygous, missense mutations in α- or β-tubulin genes are associated with a wide range of human brain malformations, known as tubulinopathies. We seek to understand whether mutation’s impact at the molecular and cellular levels scale severity malformation. Here, we focus on two valine 409 residue TUBA1A, V409I, V409A, identified patients pachygyria lissencephaly, respectively. find that ectopic expression TUBA1A -V409I/A mutants disrupt neuronal migration mice promote excessive neurite...

Despite the broadly conserved role of microtubules in chromosome segregation, we have a limited understanding how molecular features tubulin proteins contribute to underlying mechanisms. Here investigate negatively charged carboxy-terminal tail domains (CTTs) α- and β-tubulins, using series mutants that alter or ablate CTTs budding yeast. We find ablating β-CTT causes elevated rates loss cell cycle delay. Complementary live-cell imaging electron tomography show is necessary properly position...

Neurons rely on long-range trafficking of synaptic components to form and maintain the complex neural networks that encode human experience. With a single neuron capable forming thousands distinct

Abstract Developing neurons undergo dramatic morphological changes to appropriately migrate and extend axons make synaptic connections. The microtubule cytoskeleton, made of α/β-tubulin dimers, drives neurite outgrowth, promotes neuronal growth cone responses, facilitates intracellular transport critical cargoes during neurodevelopment. TUBA1A constitutes the majority α-tubulin in developing brain mutations humans cause severe malformations accompanied by varying neurological defects,...

Abstract Elementary Students’ Perceptions of Engineers: Using a Draw-an-Engineer Test to evaluate the impact classroom engineering experiences and explicit messagingAn 11-year university/public school district partnership was formed increase awareness ofengineering its opportunities for K-12 students, regardless circumstance, with goal ofbroadening participation populations underrepresented in engineering. As part thispartnership, graduate teaching fellows teach weekly hands-on activitiesand...

ABSTRACT Gain-of-function mutations in the LRRK2 gene cause Parkinson’s disease (PD), characterized by debilitating motor and non-motor symptoms. Increased phosphorylation of a subset RAB GTPases is implicated PD pathogenesis. We find that increased RAB3A, cardinal synaptic vesicle precursor (SVP) protein, disrupts anterograde axonal transport SVPs iPSC-derived human neurons (iNeurons) expressing hyperactive -p.R1441H. Knockout opposing protein phosphatase 1H ( PPM1H ) iNeurons phenocopies...

SUMMARY ‘Tubulinopathies’ are severe human brain malformations associated with mutations in tubulin genes. Despite the identification of many patients, we do not understand how these impact microtubule cytoskeleton, changes to function lead malformations, or different isotypes regulate microtubules support normal neurodevelopment. TUBA1A α-tubulin is most commonly affected isotype tubulinopathy patients. Heterozygous have been identified patients diverse cortical including...

ABSTRACT Heterozygous, missense mutations in α- or β-tubulin genes are associated with a wide range of human brain malformations, known as tubulinopathies. We seek to understand whether mutation’s impact at the molecular and cellular levels scale severity malformation. Here we focus on two valine 409 residue TUBA1A, V409I V409A, identified patients pachygyria lissencephaly, respectively. find that ectopic expression TUBA1A -V409I/A mutants disrupt neuronal migration mice promote excessive...