Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A

Autor: Peng Peng Zhu, Tyler Mark Pierson, Craig Blackstone, Kyle R. Denton, Xue-Jun Li
Rok vydání: 2014
Předmět:
Models
Molecular
Protein Conformation
Cellular differentiation
DNA Mutational Analysis
Neurodegenerative
medicine.disease_cause
Medical and Health Sciences
Models
Spastic Paraplegia
2.1 Biological and endogenous factors
Aetiology
Axon
Child
Induced pluripotent stem cell
Genetics (clinical)
Neurons
Genetics & Heredity
Genetics
Mutation
Stem Cell Research - Induced Pluripotent Stem Cell - Human
Cell Differentiation
Articles
General Medicine
Biological Sciences
Tubulin Modulators
Cell biology
Protein Transport
Hereditary
medicine.anatomical_structure
Child
Preschool
Neurological
Female
Atlastin
Heterozygote
Hereditary spastic paraplegia
1.1 Normal biological development and functioning
Molecular Sequence Data
Induced Pluripotent Stem Cells
Biology
Cell Line
GTP-Binding Proteins
Underpinning research
Microtubule
medicine
Animals
Humans
Amino Acid Sequence
Stem Cell Research - Embryonic - Human
Preschool
Molecular Biology
Stem Cell Research - Induced Pluripotent Stem Cell
Spastic Paraplegia
Hereditary
Neurosciences
Membrane Proteins
Molecular
Stem Cell Research
medicine.disease
Axons
Forebrain
Sequence Alignment
Zdroj: Human molecular genetics, vol 23, iss 21
ISSN: 1460-2083
0964-6906
DOI: 10.1093/hmg/ddu280
Popis: Hereditary spastic paraplegias are a large, diverse group of neurological disorders (SPG1-71) with the unifying feature of prominent lower extremity spasticity, owing to a length-dependent axonopathy of corticospinal motor neurons. The most common early-onset form of pure, autosomal dominant hereditary spastic paraplegia is caused by mutation in the ATL1 gene encoding the atlastin-1 GTPase, which mediates homotypic fusion of ER tubules to form the polygonal ER network. We have identified a p.Pro342Ser mutation in a young girl with pure SPG3A. This residue is in a critical hinge region of atlastin-1 between its GTPase and assembly domains, and it is conserved in all known eukaryotic atlastin orthologs. We produced induced pluripotent stem cells from skin fibroblasts and differentiated these into forebrain neurons to generate a human neuronal model for SPG3A. Axons of these SPG3A neurons showed impaired growth, recapitulating axonal defects in atlastin-1-depleted rat cortical neurons and impaired root hair growth in loss-of-function mutants of the ATL1 ortholog rhd3 in the plant Arabidopsis. Both the microtubule cytoskeleton and tubular ER are important for mitochondrial distribution and function within cells, and SPG3A neurons showed alterations in mitochondrial motility. Even so, it is not clear whether this change is involved in disease pathogenesis. The SPG3A axon growth defects could be rescued with microtubule-binding agents, emphasizing the importance of tubular ER interactions with the microtubule cytoskeleton in hereditary spastic paraplegia pathogenesis. The prominent alterations in axon growth in SPG3A neurons may represent a particularly attractive target for suppression in screens for novel pharmacologic agents.
Databáze: OpenAIRE
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