Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.4.4 (kinesin)
 5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CAG/polyglutamine (polyGln)-related diseases include nine different members that together form the most common class of inherited neurodegenerative disorders; neurodegeneration is linked to the same type of mutation, found in unrelated genes, consisting of an abnormal expansion of a polyGln tract normally present in the wild-type proteins. Nuclear, cytoplasmic, or neuropil aggregates are detectable in CAG/polyGln-related diseases, but their role is still debated. Alteration of the androgen receptor (AR), one of these proteins, has been linked to spinal and bulbar muscular atrophy, an X-linked recessive disease characterized by motoneuronal death. By using immortalized motoneuronal cells (the neuroblastoma-spinal cord cell line NSC34), we analyzed neuropil aggregate formation and toxicity: green fluorescent protein-tagged wild-type or mutated ARs were cotransfected into NSC34 cells with a blue fluorescent protein tagged to mitochondria. Altered mitochondrial distribution was observed in neuronal processes containing aggregates; occasionally, neuropil aggregates and mitochondrial concentration corresponded to axonal swelling. Neuropil aggregates also impaired the distribution of the motor protein kinesin. These data suggest that neuropil aggregates may physically alter neurite transport and thus deprive neuronal processes of factors or components that are important for axonal and dendritic functions. The soma may then be affected, leading to neuronal dysfunctions and possibly to cell death.
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PMID:Androgen receptor with elongated polyglutamine tract forms aggregates that alter axonal trafficking and mitochondrial distribution in motor neuronal processes. 1220 33

Expansion of the polyglutamine (polyQ) stretch in the androgen receptor (AR) protein leads to spinal and bulbar muscular atrophy (SBMA), a neurodegenerative disease characterized by lower motor neuron degeneration. The pathogenic mechanisms underlying SBMA remain unknown, but recent experiments show that inhibition of fast axonal transport (FAT) by polyQ-expanded proteins, including polyQ-AR, represents a new cytoplasmic pathogenic lesion. Using pharmacological, biochemical and cell biological experiments, we found a new pathogenic pathway that is affected in SBMA and results in compromised FAT. PolyQ-AR inhibits FAT in a human cell line and in squid axoplasm through a pathway that involves activation of cJun N-terminal kinase (JNK) activity. Active JNK phosphorylated kinesin-1 heavy chains and inhibited kinesin-1 microtubule-binding activity. JNK inhibitors prevented polyQ-AR-mediated inhibition of FAT and reversed suppression of neurite formation by polyQ-AR. We propose that JNK represents a promising target for therapeutic interventions in SBMA.
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PMID:JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport. 1675 63

Motor neurons typically have very long axons, and fine-tuning axonal transport is crucial for their survival. The obstruction of axonal transport is gaining attention as a cause of neuronal dysfunction in a variety of neurodegenerative motor neuron diseases. Depletions in dynein and dynactin-1, motor molecules regulating axonal trafficking, disrupt axonal transport in flies, and mutations in their genes cause motor neuron degeneration in humans and rodents. Axonal transport defects are among the early molecular events leading to neurodegeneration in mouse models of amyotrophic lateral sclerosis (ALS). Gene expression profiles indicate that dynactin-1 mRNA is downregulated in degenerating spinal motor neurons of autopsied patients with sporadic ALS. Dynactin-1 mRNA is also reduced in the affected neurons of a mouse model of spinal and bulbar muscular atrophy, a motor neuron disease caused by triplet CAG repeat expansion in the gene encoding the androgen receptor. Pathogenic androgen receptor proteins also inhibit kinesin-1 microtubule-binding activity and disrupt anterograde axonal transport by activating c-Jun N-terminal kinase. Disruption of axonal transport also underlies the pathogenesis of spinal muscular atrophy and hereditary spastic paraplegias. These observations suggest that the impairment of axonal transport is a key event in the pathological processes of motor neuron degeneration and an important target of therapy development for motor neuron diseases.
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PMID:Disruption of axonal transport in motor neuron diseases. 2231 14