Armen J. Moughamian

Retrograde axonal transport: pathways to cell death?

Active transport along the axon is crucial to the neuron. Motor-driven transport supplies the distal synapse with newly synthesized proteins and lipids, and clears damaged or misfolded proteins. Microtubule motors also drive long-distance signaling along the axon via signaling endosomes. Although positive signaling initiated by neurotrophic factors has been well-studied, recent research has focused on stress-signaling along the axon. Here, the connections between axonal transport alterations and neurodegeneration are discussed, including evidence for defective transport of vesicles, mitochondria, degradative organelles, and signaling endosomes in models of amyotrophic lateral sclerosis, Huntingtons, Parkinsons and Alzheimers disease. Defects in transport are sufficient to induce neurodegeneration, but recent progress suggests that changes in retrograde signaling pathways correlate with rapidly progressive neuronal cell death.

Axonal Transport: Cargo-Specific Mechanisms of Motility and Regulation

Axonal transport is essential for neuronal function, and many neurodevelopmental and neurodegenerative diseases result from mutations in the axonal transport machinery. Anterograde transport supplies distal axons with newly synthesized proteins and lipids, including synaptic components required to maintain presynaptic activity. Retrograde transport is required to maintain homeostasis by removing aging proteins and organelles from the distal axon for degradation and recycling of components. Retrograde axonal transport also plays a major role in neurotrophic and injury response signaling. This review provides an overview of axonal transport pathways and discusses their role in neuronal function.

Ordered recruitment of dynactin to the microtubule plus-end is required for efficient initiation of retrograde axonal transport.

Long-range retrograde axonal transport in neurons is driven exclusively by the microtubule motor cytoplasmic dynein. The efficient initiation of dynein-mediated transport from the distal axon is critical for normal neuronal function, and neurodegenerative disease-associated mutations have been shown to specifically disrupt this process. Here, we examine the role of dynamic microtubules and microtubule plus-end binding proteins (+TIPs) in the initiation of dynein-mediated retrograde axonal transport using live-cell imaging of cargo motility in primary mouse dorsal root ganglion neurons. We show that end-binding (EB)-positive dynamic microtubules are enriched in the distal axon. The +TIPs EB1, EB3, and cytoplasmic linker protein-170 (CLIP-170) interact with these dynamic microtubules, recruiting the dynein activator dynactin in an ordered pathway, leading to the initiation of retrograde transport by the motor dynein. Once transport has initiated, however, neither the EBs nor CLIP-170 are required to maintain transport flux along the mid-axon. In contrast, the +TIP Lis1 activates transport through a distinct mechanism and is required to maintain processive organelle transport along both the distal and mid-axon. Further, we show that the EB/CLIP-170/dynactin-dependent mechanism is required for the efficient initiation of transport from the distal axon for multiple distinct cargos, including mitochondria, Rab5-positive early endosomes, late endosomes/lysosomes, and TrkA-, TrkB-, and APP-positive organelles. Our observations indicate that there is an essential role for +TIPs in the regulation of retrograde transport initiation in the neuron.

Dynactin Subunit p150Glued Is a Neuron-Specific Anti-Catastrophe Factor

The dynein partner dynactin not only binds to microtubules, but is found to potently influence microtubule dynamics in neurons.

Angiotensin II AT1 Receptor Blockade Decreases Lipopolysaccharide-Induced Inflammation in the Rat Adrenal Gland

Peripheral administration of bacterial endotoxin [lipopolysaccharide (LPS)] to rodents produces an innate immune response and hypothalamic-pituitary-adrenal axis stimulation. Renin-angiotensin-aldosterone system inhibition by angiotensin II AT1 receptor blockade has antiinflammatory effects in the vasculature. We studied whether angiotensin II receptor blockers (ARBs) prevent the LPS response. We focused on the adrenal gland, one organ responsive to LPS and expressing a local renin-angiotensin-aldosterone system. LPS (50 microg/kg, ip) produced a generalized inflammatory response with increased release of TNF-alpha and IL-6 to the circulation, enhanced adrenal aldosterone synthesis and release, and enhanced adrenal cyclooxygenase-2, IL-6, and TNF-alpha gene expression. ACTH and corticosterone release were also increased by LPS. Pretreatment with the ARB candesartan (1 mg/kg.d, sc for 3 d before the LPS administration) decreased LPS-induced cytokine release to the circulation, adrenal aldosterone synthesis and release, and cyclooxygenase-2 and IL-6 gene expression. Candesartan did not prevent the LPS-induced ACTH and corticosterone release. Our results suggest that AT1 receptors are essential for the development of the full innate immune and stress responses to bacterial endotoxin. The ARB decreased the general peripheral inflammatory response to LPS, partially decreased the inflammatory response in the adrenal gland, prevented the release of the pro-inflammatory hormone aldosterone, and protected the antiinflammatory effects of glucocorticoid release. An unrestricted innate immune response to the bacterial endotoxin may have deleterious effects for the organism and may lead to development of chronic inflammatory disease. We postulate that the ARBs may have therapeutic effects on inflammatory conditions.

Expression and transport of Angiotensin II AT1 receptors in spinal cord, dorsal root ganglia and sciatic nerve of the rat

To clarify the role of Angiotensin II in the regulation of peripheral sensory and motor systems, we initiated a study of the expression, localization and transport of Angiotensin II receptor types in the rat sciatic nerve pathway, including L(4)-L(5) spinal cord segments, the corresponding dorsal root ganglia (DRGs) and the sciatic nerve. We used quantitative autoradiography for AT(1) and AT(2) receptors, and in situ hybridization to detect AT(1A), AT(1B) and AT(2) mRNAs. We found substantial expression and discrete localization of Angiotensin II AT(1) receptors, with much higher numbers in the grey than in the white matter. A very high AT(1) receptor expression was detected in the superficial dorsal horns and in neuronal clusters of the DRGs. Expression of AT(1A) mRNA was significantly higher than that of AT(1B). AT(1) receptor binding and AT(1A) and AT(1B) mRNAs were especially prominent in ventral horn motor neurons, and in the DRG neuronal cells. Unilateral dorsal rhizotomy significantly reduced AT(1) receptor binding in the ipsilateral side of the superficial dorsal horn, indicating that a substantial number of dorsal horn AT(1) receptors have their origin in the DRGs. After ligation of the sciatic nerve, there was a high accumulation of AT(1) receptors proximal to the ligature, a demonstration of anterograde receptor transport. We found inconsistent levels of AT(2) receptor binding and mRNA. Our results suggest multiple roles of Angiotensin II AT(1) receptors in the regulation of sensory and motor functions.

Synaptic Vesicle Distribution by Conveyor Belt

The equal distribution of synaptic vesicles among synapses along the axon is critical for robust neurotransmission. Wong et al. show that the continuous circulation of synaptic vesicles throughout the axon driven by molecular motors ultimately yields this even distribution.

Cytoplasmic dynein dysfunction and neurodegenerative disease

Publisher Summary Active, directed transport along cytoplasmic microtubules is a characteristic feature of mammalian cells. The transport of organelles, vesicles, and proteins along the microtubule cytoskeleton is driven by both kinesins and cytoplasmic dynein. Neurons are uniquely vulnerable to defects in dynein function. Mutations in cytoplasmic dynein and its activator dynactin result in neurological defects in humans as well as in model organisms including drosophila and mice. The important role of the dynein motor in intracellular trafficking and transport makes it likely that defects in this pathway contribute to a number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). The identification of cytoplasmic dynein as an essential minus-end-directed motor in higher eukaryotes has led to a much deeper understanding of the role of active transport in the neuron. This chapter reviews the critical roles dynein plays in neurons. Following this, it discusses the effects that dynein and dynactin mutations have on neuronal function. Finally, it deals with the neurodegenerative diseases in which dynein dysfunction is not the proximal cause but may be a key contributor to the pathological state. The significance of these questions to neurodegenerative disease is becoming increasingly clear with the identification of human mutations in the dynein-associated protein dynactin, Lis1, Rab7, and bIII spectrin, which is now a rapidly progressing field.

Teaching NeuroImages: Artery of Percheron aneurysm masquerading as ICH spot sign

A 50-year-old Japanese woman presented with left thalamic intracerebral hemorrhage (ICH). CT angiography demonstrated an ICH spot sign and intracranial vasculopathy consistent with Moyamoya disease (figure 1). Conventional angiography demonstrated that the spot sign was actually a pseudoaneurysm arising from the artery of Percheron (figure 2). Intracranial aneurysms may complicate Moyamoya disease and occur at the circle of Willis, distal peripheral arteries, or Moyamoya vessels at a ratio of 3:1:1.1 Aneurysms in thalamo-perforating arteries are rare2 and an artery of Percheron aneurysm in Moyamoya disease has not been reported. In Moyamoya disease, presence of a spot sign should prompt consideration for angiography.