Function and Regulation of ALDH1A1-Positive Nigrostriatal Dopaminergic Neurons in Motor Control and Parkinson’s Disease

Dopamine is an important chemical messenger in the brain, which modulates movement, reward, motivation, and memory. Different populations of neurons can produce and release dopamine in the brain and regulate different behaviors. Here we focus our discussion on a small but distinct group of dopamine-producing neurons, which display the most profound loss in the ventral substantia nigra pas compacta of patients with Parkinson’s disease. This group of dopaminergic neurons can be readily identified by a selective expression of aldehyde dehydrogenase 1A1 (ALDH1A1) and accounts for 70% of total nigrostriatal dopaminergic neurons in both human and mouse brains. Recently, we presented the first whole-brain circuit map of these ALDH1A1-positive dopaminergic neurons and reveal an essential physiological function of these neurons in regulating the vigor of movement during the acquisition of motor skills. In this review, we first summarize previous findings of ALDH1A1-positive nigrostriatal dopaminergic neurons and their connectivity and functionality, and then provide perspectives on how the activity of ALDH1A1-positive nigrostriatal dopaminergic neurons is regulated through integrating diverse presynaptic inputs and its implications for potential Parkinson’s disease treatment.

The genetics of Huntington’s disease

This chapter describes the nature of the genetic mistake. The genetic code, or DNA molecule, is wound up onto structures called chromosomes. The gene for HD is located on chromosome 4. As we have two copies of our genes the chromosomes are in pairs. Only one copy of the HD has to be abnormal to cause the condition. This results in a pattern of inheritance called autosomal dominant and both males and females can be affected. Genes code for proteins; the protein encoded by the HD gene is called huntingtin. Proteins are made of building blocks called amino acids. The gene for HD has an expansion of the genetic code for glutamine. Therefore, abnormal huntingtin has an expansion of the number of glutamines. The genetic code for glutamine is CAG so the mistake in the gene is sometimes called a CAG repeat expansion disorder or in referring to the protein it is called a polyglutamine repeat expansion. The gene is in one part of the cell and the protein-making machinery is in another part of the cell so a chemical messenger is required which is called RNA. Explaining this is important for understanding some current clinical trials

How ribbons make ‘sense’ for vision

The processing of light by the retina and brain provides the basis for visual perception. Photons are captured and converted to electrical signals by rod and cone photoreceptor cells in the retina. These electrical signals are converted to chemical signals for transmission to downstream neurons. This article provides an overview of the mechanisms involved in transmitting light responses from rods and cones. Chemical signalling occurs at synapses between neurons. In keeping with many other neurons, the chemical messenger released by photoreceptors is the amino acid glutamate, which is packaged into small spherical vesicles. Each photoreceptor synaptic terminal has thousands of synaptic vesicles. Some of these vesicles are attached to the face of planar structures known as ribbons. Ribbons capture and deliver vesicles to release sites at the bottom of the ribbon. Upon stimulation, vesicles fuse with the cell membrane and release their contents. Glutamate molecules diffuse through the extracellular space to reach specialized receptors that regulate the activity of downstream neurons. We discuss how rates of vesicle attachment to ribbons, delivery of vesicles down the ribbon and the release of glutamate shape the information provided to downstream neurons in the visual system.

Recommendations for the Treatment of Parkinson's Disease

Parkinson's disease is a progressive disorder of the nervous system characterized by trembling or shaking of a limb, rigidity or stiffness of limbs, an inability to move, and impaired balance and coordination. Most symptoms begin to occur when neurons that produce dopamine in the substantia nigra of our brain die or become impaired. Dopamine is a chemical messenger that sends signals to our brain to produce smooth muscle movements. Without the neurons that create dopamine, our brain becomes unable to produce these muscle movements. Another pathological feature is the appearance of intracytoplasmic inclusions (Lewy bodies) in the remaining, intact nigral neurons.

Thermostabilization and purification of the human dopamine transporter (hDAT) in an inhibitor and allosteric ligand bound conformation

The human dopamine transporter(hDAT) plays a major role in dopamine homeostasis and regulation of neurotransmission by clearing dopamine from the extracellular space using secondary active transport. Dopamine is an essential monoamine chemical messenger that regulates reward seeking behavior, motor control, hormonal release, and emotional response in humans. Psychostimulants such as cocaine primarily target the central binding site of hDAT and lock the transporter in an outward-facing conformation, thereby inhibiting dopamine reuptake. The inhibition of dopamine reuptake leads to accumulation of dopamine in the synapse causing heightened signaling. In addition, hDAT is implicated in various neurological disorders and disease-associated neurodegeneration. Despite its significance, the molecular architecture of hDAT and its various conformational states are poorly understood. Instability of hDAT in detergent micelles has been a limiting factor in its successful biochemical, biophysical, and structural characterization. To overcome this hurdle, first we identified ligands that stabilize hDAT in detergent micelles. Then, we screened ∼200 single residue mutants of hDAT using high-throughput scintillation proximity assay, and identified a thermostable variant(I248Y). Here we report a robust strategy to overexpress and successfully purify a thermostable variant of hDAT in an inhibitor and allosteric ligand bound conformation.

Biodiversity of CS–proteoglycan sulphation motifs: chemical messenger recognition modules with roles in information transfer, control of cellular behaviour and tissue morphogenesis

Chondroitin sulphate (CS) glycosaminoglycan chains on cell and extracellular matrix proteoglycans (PGs) can no longer be regarded as merely hydrodynamic space fillers. Overwhelming evidence over recent years indicates that sulphation motif sequences within the CS chain structure are a source of significant biological information to cells and their surrounding environment. CS sulphation motifs have been shown to interact with a wide variety of bioactive molecules, e.g. cytokines, growth factors, chemokines, morphogenetic proteins, enzymes and enzyme inhibitors, as well as structural components within the extracellular milieu. They are therefore capable of modulating a panoply of signalling pathways, thus controlling diverse cellular behaviours including proliferation, differentiation, migration and matrix synthesis. Consequently, through these motifs, CS PGs play significant roles in the maintenance of tissue homeostasis, morphogenesis, development, growth and disease. Here, we review (i) the biodiversity of CS PGs and their sulphation motif sequences and (ii) the current understanding of the signalling roles they play in regulating cellular behaviour during tissue development, growth, disease and repair.

Cooperation of the haves and the have-nots

Upon starvation, Dictyostelium discoideum (D.d.) exhibit social behavior mediated by the chemical messenger cyclic adenosine monophosphate (cAMP). Large scale cAMP waves synchronize the population of starving cells and enable them to aggregate and form a multi-cellular organism. Here, we explore the effect of cell-to-cell variability in the production of cAMP on aggregation. We create a mixture of extreme cell-to-cell variability by mixing a few cells that produce cAMP (haves) with a majority of mutants that cannot produce cAMP (have-nots). Surprisingly, such mixtures aggregate, although each population on its own cannot aggregate. We show that (1) a lack of divalent ions kills the haves at low densities and (2) the have-nots supply the cAMP degrading enzyme, phosphodiesterase, which, in the presence of divalent ions, enables the mixture to aggregate. Our results suggest that a range of degradation rates induces optimal aggregation. The haves and the have-nots cooperate by sharing complementary resources.

The evidence for open and closed exocytosis as the primary release mechanism

Exocytosis is the fundamental process by which cells communicate with each other. The events that lead up to the fusion of a vesicle loaded with chemical messenger with the cell membrane were the subject of a Nobel Prize in 2013. However, the processes occurring after the initial formation of a fusion pore are very much still in debate. The release of chemical messenger has traditionally been thought to occur through full distention of the vesicle membrane, hence assuming exocytosis to be all or none. In contrast to the all or none hypothesis, here we discuss the evidence that during exocytosis the vesicle-membrane pore opens to release only a portion of the transmitter content during exocytosis and then close again. This open and closed exocytosis is distinct from kiss-and-run exocytosis, in that it appears to be the main content released during regular exocytosis. The evidence for this partial release via open and closed exocytosis is presented considering primarily the quantitative evidence obtained with amperometry.