The spinal muscular atrophy mouse model, SMAΔ7, displays altered axonal transport without global neurofilament alterations

Dale, Jeffrey M.; Shen, Hongxing; Barry, Devin M.; Garcia, Virginia B.; Rose, Ferrill F.; Lorson, Christian L.; Garcia, Michael L.

doi:10.1007/s00401-011-0848-5

Cited by 33 publications

(38 citation statements)

References 29 publications

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“…But the relevance of kinesin-deficient Drosophila to motor neuropathies extends beyond diseases caused by mutant kinesin to additional diseases in which axonal transport is compromised and axonal swellings are observed. These diseases include amyotrophic lateral sclerosis (ALS) [83], [84], Huntington’s disease [85], [86], Parkinson’s disease [87], [88], forms of HSP in addition to SPG10 [82], [89], and SMA [90]–[92]. Small molecules that suppress the larval locomotion defect of kinesin-deficient Drosophila therefore merit evaluation as candidate therapeutics for such motor neuropathies.…”

Section: Discussionmentioning

confidence: 99%

Small Molecule Suppressors of Drosophila Kinesin Deficiency Rescue Motor Axon Development in a Zebrafish Model of Spinal Muscular Atrophy

Gassman¹,

Liang

Bhoite

et al. 2013

PLoS ONE

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Proximal spinal muscular atrophy (SMA) is the most common inherited motor neuropathy and the leading hereditary cause of infant mortality. Currently there is no effective treatment for the disease, reflecting a need for pharmacologic interventions that restore performance of dysfunctional motor neurons or suppress the consequences of their dysfunction. In a series of assays relevant to motor neuron biology, we explored the activities of a collection of tetrahydroindoles that were reported to alter the metabolism of amyloid precursor protein (APP). In Drosophila larvae the compounds suppressed aberrant larval locomotion due to mutations in the Khc and Klc genes, which respectively encode the heavy and light chains of kinesin-1. A representative compound of this class also suppressed the appearance of axonal swellings (alternatively termed axonal spheroids or neuritic beads) in the segmental nerves of the kinesin-deficient Drosophila larvae. Given the importance of kinesin-dependent transport for extension and maintenance of axons and their growth cones, three members of the class were tested for neurotrophic effects on isolated rat spinal motor neurons. Each compound stimulated neurite outgrowth. In addition, consistent with SMA being an axonopathy of motor neurons, the three axonotrophic compounds rescued motor axon development in a zebrafish model of SMA. The results introduce a collection of small molecules as pharmacologic suppressors of SMA-associated phenotypes and nominate specific members of the collection for development as candidate SMA therapeutics. More generally, the results reinforce the perception of SMA as an axonopathy and suggest novel approaches to treating the disease.

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Section: Discussionmentioning

confidence: 99%

Small Molecule Suppressors of Drosophila Kinesin Deficiency Rescue Motor Axon Development in a Zebrafish Model of Spinal Muscular Atrophy

Gassman¹,

Liang

Bhoite

et al. 2013

PLoS ONE

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“…On d18.5 of gestation, pregnant females were sacrificed by using a CO 2 chamber and cervical dislocation. Fetuses from these mothers were genotyped using tail biopsies as previously described [16]. All experiments were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of the University of Missouri.…”

Section: Methodsmentioning

confidence: 99%

Placental development in a mouse model of spinal muscular atrophy

Caesar

Dale

Osman

et al. 2016

Biochemical and Biophysical Research Communications

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Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder, leading to fatal loss of motor neurons. It is caused by loss of function of the SMN gene, which is expressed throughout the body, and there is increasing evidence of dysfunction in non-neuronal tissues. Birthweight is one of most powerful prognostic factors for infants born with SMA, and intrauterine growth restriction is common. In the SMNΔ7 mouse model of SMA, pups with the disease lived 25% longer when their mothers were fed a higher fat, “breeder” diet. The placenta is responsible for transport of nutrients from mother to fetus, and is a major determinant of fetal growth. Thus, the present study tested the hypothesis that placental development is impaired in SMNΔ7 conceptuses. Detailed morphological characterization revealed no defects in SMNΔ7 placental development, and expression of key transcription factors regulating mouse placental development was unaffected. The intrauterine growth restriction observed in SMA infants likely does not result from impaired placental development.

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“…Moreover, decreased transport was not due to impaired kinesin function; indeed, kinesin heavy chain Kif5c, which is predominantly utilized in kinesin oligomer formation in motor neurons, was not altered in SMAΔ7 mice. Accordingly, reduced synaptic vesicle densities at SMAΔ7 NMJs may be a consequence of the reduced synaptic vesicle transport and release that dropped by 50% at P14 (21). Accordingly, reduced synaptic vesicle densities at SMAΔ7 NMJs may be a consequence of the reduced synaptic vesicle transport and release that dropped by 50% at P14 (21).…”

Section: Axonal Transport Alteration In Smamentioning

confidence: 99%

“…Accordingly, reduced synaptic vesicle densities at SMAΔ7 NMJs may be a consequence of the reduced synaptic vesicle transport and release that dropped by 50% at P14 (21). As shown by Dale and collaborators for motor neurons (21), abnormal accumulation of phosphorylated and nonphosphorylated NFs as well as microtubule proteins was detected (46) in the retinal preparation from Smn 2B/− mice (24), suggesting that aggregation of NFs is a general phenomenon in the pathology of SMA, which is not restricted to the motor neurons. As shown by Dale and collaborators for motor neurons (21), abnormal accumulation of phosphorylated and nonphosphorylated NFs as well as microtubule proteins was detected (46) in the retinal preparation from Smn 2B/− mice (24), suggesting that aggregation of NFs is a general phenomenon in the pathology of SMA, which is not restricted to the motor neurons.…”

Section: Axonal Transport Alteration In Smamentioning

confidence: 99%

Spinal Muscular Atrophy: New Findings for an Old Pathology

Bottai

Adami

2013

Brain Pathology

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Understanding the events that are responsible for a disease is mandatory for setting up a therapeutic strategy. Although spinal muscular atrophy (SMA) is considered a rare neurodegenerative pathology, its impact in our society is really devastating as it strikes young people from birth onward, and it affects their families either emotionally or financially. Moreover, it requires intensive care for the children, and this diverts both parents and relatives from their occupations. Each neuron is very different from one another; therefore, in a neurodegenerative disease, the population of axons, synapses and cell bodies degenerate asynchronously, and subpopulations of neurons have different vulnerabilities. The knowledge of the sequence of events along the lengths of individual neurons is crucial to understand if each synapse degenerates before the corresponding axon, or if each axon degenerates before the corresponding cell body. Early degeneration of one neuronal compartment in disease often reflects molecular defects somewhere else. Up until now, SMA is considered mostly a lower motor neuron disease caused by the loss-of-function mutations in the SMN1 gene; here, we inspect other features that can be altered by this defect, such as the cross talk between muscle and motor neuron and the role of physical inactivity.

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The spinal muscular atrophy mouse model, SMAΔ7, displays altered axonal transport without global neurofilament alterations

Cited by 33 publications

References 29 publications

Small Molecule Suppressors of Drosophila Kinesin Deficiency Rescue Motor Axon Development in a Zebrafish Model of Spinal Muscular Atrophy

Small Molecule Suppressors of Drosophila Kinesin Deficiency Rescue Motor Axon Development in a Zebrafish Model of Spinal Muscular Atrophy

Placental development in a mouse model of spinal muscular atrophy

Spinal Muscular Atrophy: New Findings for an Old Pathology

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