The genetics of axonal transport and axonal transport disorders

Neurons are specialized cells with a complex architecture that includes elaborate dendritic branches and a long, narrow axon that extends from the cell body to the synaptic terminal. The organized transport of essential biological materials throughout the neuron is required to support its growth, function, and viability. In this review, we focus on insights that have emerged from the genetic analysis of long-distance axonal transport between the cell body and the synaptic terminal. We also discuss recent genetic evidence that supports the hypothesis that disruptions in axonal transport may cause or dramatically contribute to neurodegenerative diseases.     

Axonal transport versus dendritic transport

Neurons have polarized processes for information output and input, axons, and dendrites. This polarized architecture is essential for the neuronal function. An increasing number of molecular components that mediate neuronal polarity establishment have been characterized over the past few years. The vast majority of these molecules include proteins that act in scaffolding protein complexes to sustain the polarized anchoring of molecules. In addition, more signaling and cytoskeleton-associated proteins have been proposed for establishment of polarity. It has become evident that dendritic and axonal transport of molecules depends on scaffolding/adaptor proteins that are recognized by molecular motors. Current and future research in the neuronal cell polarity will be focused on how different cargo molecules transmit their signals to the cytoskeleton and change its dynamic properties to affect the rate and direction of vesicular movement. In this review, we discuss recent evidence that scaffolding proteins can regulate motor motility and guidance by a mechanism of substrate-cytoskeletal coupling and amino acid modifications during polarized transport.     

Phosphate transport and signaling

The discovery of phosphate (Pi) transporter genes has provided a basis for the molecular study of the complex pattern of Pi transport in plants. Over the past two years, a significant amount of information has been generated on the molecular regulation of phosphate transport in plants. Recent developments in plant genomics will soon allow the complete dissection of the signal transduction pathway(s) associated with plant responses to Pi limitation in the rhizosphere.     

Membrane transport and disease

Four situations in which membrane transport is altered by disease are discussed: (a) non-specific leaks induced by poreforming agents; (b) glucose transport and cellular stress; (c) Ca⁺-ATPase and hypertension; (d) Na^– channels and HSV infection.Keynote Lecture delivered at International Symposium onBiomembranes and Disease, on 1 November 1988 at Lucknow, India     

RNA localization and transport

RNA localization serves numerous purposes from controlling development and differentiation to supporting the physiological activities of cells and organisms. After a brief introduction into the history of the study of mRNA localization I will focus on animal systems, describing in which cellular compartments and in which cell types mRNA localization was observed and studied. In recent years numerous novel localization patterns have been described, and countless mRNAs have been documented to accumulate in specific subcellular compartments. These fascinating revelations prompted speculations about the purpose of localizing all these mRNAs. In recent years experimental evidence for an unexpected variety of different functions has started to emerge. Aside from focusing on the functional aspects, I will discuss various ways of localizing mRNAs with a focus on the mechanism of active and directed transport on cytoskeletal tracks. Structural studies combined with imaging of transport and biochemical studies have contributed to the enormous recent progress, particularly in understanding how dynein/dynactin/BicD (DDB) dependent transport on microtubules works. This transport process actively localizes diverse cargo in similar ways to the minus end of microtubules and, at least in flies, also individual mRNA molecules. A sophisticated mechanism ensures that cargo loading licenses processive transport.     

Glucose transport and apoptosis

The transport and metabolism of glucose modify programmed cell death in a number of different cell types. This review presents three cell death paradigms that link a decrease in glucose transport to apoptosis. Although these pathways overlap, the glucose-dependent stimuli that trigger cell death differ. These paradigms include glucose deprivation-induced ATP depletion and stimulation of the mitochondrial death pathway cascade; glucose deprivation-induced oxidative stress and triggering of Bax-associated events including the JNK/MAPK signalling pathways; and finally hypoglycemia-regulated expression of HIF-1, stabilization of p53 leading to an increase in p53-associated apoptosis. Several examples of each paradigm are presented. Future studies of glucose transport-associated apoptotic events will allow better understanding of the role of cellular metabolism in programmed cell death.     

Beta-granule transport and exocytosis

Regulated beta -granule exocytosis is critical for the ability of the beta -cell to finely control body glucose homeostasis. This is now understood to be a multistage process whereby beta -granules are transported from biosynthetic/storage sites in the cell cytoplasm and targeted to specific regions of the plasma membrane. Exocytosis is achieved when these granules are triggered to fuse with the membrane by an elevated cytosolic Ca(2+). Dramatic advances have been made recently in our understanding of the protein-protein interactions and regulatory signals that govern intracellular transport and fusion. Although best understood for exocytosis from neurons and neuroendocrine cells, similar processes are thought to be conserved in the beta -cell.     

Mercury transport and resistance

Resistance to mercuric ions in bacteria is conferred by mercuric reductase, which reduces Hg(II) to Hg(0) in the cytoplasmic compartment. Specific mercuric ion transport systems exist to take up Hg(II) salts and deliver them to the active site of the reductase. This short review discusses the role of transport proteins in resistance and the mechanism of transfer of Hg(II) between the mercury-resistance proteins.     

Nitrate transport and signalling

Physiological measurements of nitrate (NO(3)(-)) uptake by roots have defined two systems of high and low affinity uptake. In Arabidopsis, genes encoding both of these two uptake systems have been identified. Most is known about the high affinity transport system (HATS) and its regulation and yet measurements of soil NO(3)(-) show that it is more often available in the low affinity range above 1 mM concentration. Several different regulatory mechanisms have been identified for AtNRT2.1, one of the membrane transporters encoding HATS; these include feedback regulation of expression, a second component protein requirement for membrane targeting and phosphorylation, possibly leading to degradation of the protein. These various changes in the protein may be important for a second function in sensing NO(3)(-) availability at the surface of the root. Another transporter protein, AtNRT1.1 also has a role in NO(3)(-) sensing that, like AtNRT2.1, is independent of their transport function. From the range of concentrations present in the soil it is proposed that the NO(3)(-)-inducible part of HATS functions chiefly as a sensor for root NO(3)(-) availability. Two other key NO(3)(-) transport steps for efficient nitrogen use by crops, efflux across membranes and vacuolar storage and remobilization, are discussed. Genes encoding vacuolar transporters have been isolated and these are important for manipulating storage pools in crops, but the efflux system is yet to be identified. Consideration is given to how well our molecular and physiological knowledge can be integrated as well to some key questions and opportunities for the future.     

Determinants of cation transport selectivity: Equilibrium binding and transport kinetics

ConclusionThe equilibrium ion-binding properties of ion channels and transporters can be difficult to discern from crystal structures alone, as proteins often adopt different lowest energy states depending on the ions bound. In cases where transport is slow, their inherent ion-binding preferences can be used to infer their transport preferences. However, in cases where transport is fast, the transport selectivity can hide their equilibrium preferences by accentuating the kinetics of ions hopping through a channel over its inherent ion-binding preferences. Thus, depending on the arrangement of ion-binding sites in a channel’s selectivity filter, one can achieve either selective or nonselective ion transport.The equilibrium K⁺ selectivity of some nonselective channels suggests a potential mechanism whereby they could evolve into a fast K⁺-selective channel. K⁺ channels and nonselective channels like CNG and HCN are related to one another in both sequence and structure, suggesting an evolutionary link between them. Swap experiments show that only a few mutations separate a nonselective channel from a K⁺-selective channel. One might imagine an evolutionary path between these channels in which the equilibrium preference for a K⁺ ion in a nonselective channel evolves into a K⁺-selective channel through these few mutations to create the selective ion queue. Alternatively, a slow single-ion channel with an equilibrium and transport preference for K⁺ ions could be transformed into a fast multi-ion channel through mutations that create a queue of K⁺-selective ion-binding sites, as is seen in most K⁺ channels studied to date.In the case of multi-ion selectivity filters, such as those found in K⁺ channels, the selectivity filter can be viewed as the active site that interacts with different queues of ions and water molecules. At least three properties emerge from multi-ion queues: (1) high conductance by reducing the affinity of multiple bound ions versus single ions; (2) high selectivity by allowing disfavored ions time to dissociate back into solution; and, consequently, (3) robust selectivity in an environment where ion concentrations can change. For transporters and carriers, the equilibrium preference and slow transport naturally create robust selectivity. In all these cases, equilibrium-based ion selectivity is achieved by slowing transport enough so that the disfavored ion is able to dissociate back into solution before transport takes place.