Mechanisms of Observed Neuroprotection of Dopaminergic Neurons in Wallerian Degeneration Slow (WldS) Mice

An emerging hypothesis in Parkinson\u27s disease: PD) is that dopaminergic: DA) neurons degenerate through a dying back axonopathy wherein degeneration begins in the distal axon and progresses over time towards the cell body. Impaired axonal transport also appears to play an early, pivotal role in PD. Thus processes that delay axonal transport dysfunction and/or axonal degeneration might slow PD progression. Previously, we and others have found that the WldS mouse mutant: Wallerian degeneration-slow ), which exhibits delayed axonal degeneration after peripheral axonopathy, also protects DA terminal fields from the PD-mimetics 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: MPTP) and 6-hydroxydopamine: 6-OHDA) in vivo. To understand the mechanisms underlying WldS-mediated axonal protection, we tested whether WldS rescued DA neurons in vitro after treatment with either MPP+, the active component of MPTP, or 6-OHDA. WldS, but not its component parts, UbE4b and Nmnat1, robustly rescued neurites in dissociated DA cultures following either MPP+ or 6-OHDA treatment. To extend these results, compartmented chambers were developed such that axons could be segregated from cell bodies and dendrites. Using these devices, we found that MPP+ impaired mitochondrial, but not synaptic vesicle transport, in DA axons and that WldS rescued MPP+-mediated impairment of mitochondrial transport in DA axons. Mechanistically, this appears to be due to WldS-mediated protection from toxin-induced loss of mitochondrial membrane potential. These results extend WldS protection to CNS DA neurons and suggest that WldS confers a gain-of-function phenotype that attenuates mitochondrial dysfunction. This study, together with the large amount of evidence suggesting PD is associated with axonal dying-back , also underscores the necessity of developing therapeutics aimed at axons as well as cell bodies so as to preserve circuitry and function

WldS but not Nmnat1 protects dopaminergic neurites from MPP+ neurotoxicity

<p>Abstract</p> <p>Background</p> <p>The <it>Wld^S</it>mouse mutant ("Wallerian degeneration-slow") delays axonal degeneration in a variety of disorders including <it>in vivo </it>models of Parkinson's disease. The mechanisms underlying <it>Wld^S</it>-mediated axonal protection are unclear, although many studies have attributed <it>Wld^S</it>neuroprotection to the NAD⁺-synthesizing Nmnat1 portion of the fusion protein. Here, we used dissociated dopaminergic cultures to test the hypothesis that catalytically active Nmnat1 protects dopaminergic neurons from toxin-mediated axonal injury.</p> <p>Results</p> <p>Using mutant mice and lentiviral transduction of dopaminergic neurons, the present findings demonstrate that <it>Wld^S</it>but not Nmnat1, Nmnat3, or cytoplasmically-targeted Nmnat1 protects dopamine axons from the parkinsonian mimetic N-methyl-4-phenylpyridinium (MPP⁺). Moreover, NAD⁺synthesis is not required since enzymatically-inactive <it>Wld^S</it>still protects. In addition, NAD⁺by itself is axonally protective and together with <it>Wld^S</it>is additive in the MPP⁺model.</p> <p>Conclusions</p> <p>Our data suggest that NAD⁺and <it>Wld^S</it>act through separate and possibly parallel mechanisms to protect dopamine axons. As MPP⁺is thought to impair mitochondrial function, these results suggest that <it>Wld^S</it>might be involved in preserving mitochondrial health or maintaining cellular metabolism.</p

The parkinsonian mimetic, MPP+, specifically impairs mitochondrial transport in dopamine axons

Impaired axonal transport may play a key role in Parkinson’s disease. To test this notion, a microchamber system was adapted to segregate axons from cell bodies using green fluorescent protein-labeled mouse dopamine (DA) neurons. Transport was examined in axons challenged with the DA neurotoxin MPP(+). MPP(+) rapidly reduced overall mitochondrial motility in DA axons; among motile mitochondria, anterograde transport was slower yet retrograde transport was increased. Transport effects were specific for DA mitochondria, which were smaller and transported more slowly than their non-DA counterparts. MPP(+) did not affect synaptophysin-tagged vesicles or any other measureable moving particle. Toxin effects on DA mitochondria were not dependent upon ATP, calcium, free radical species, JNK, or caspase3/PKC pathways but were completely blocked by the thiol-anti-oxidant N-acetyl-cysteine or membrane-permeable glutathione. Since these drugs also rescued processes from degeneration, these findings emphasize the need to develop therapeutics aimed at axons as well as cell bodies to preserve “normal” circuitry and function as long as possible

Motor asymmetry and substantia nigra volume are related to spatial delayed response performance in Parkinson disease

Studies suggest motor deficit asymmetry may help predict the pattern of cognitive impairment in individuals with Parkinson disease (PD). We tested this hypothesis using a highly validated and sensitive spatial memory task, spatial delayed response (SDR), and clinical and neuroimaging measures of PD asymmetry. We predicted SDR performance would be more impaired by PD-related changes in the right side of the brain than in the left. PD (n = 35) and control (n = 28) participants performed the SDR task. PD participants either had worse motor deficits on the right (RPD) or left (LPD) side of the body. Some participants also had magnetic resonance imaging for measurement of their substantia nigra (SN) volumes. The LPD group performed worse on the SDR task than the RPD and control groups. Right SN volume accounted for a unique and significant portion of the variance in SDR error, with smaller volume predicting poorer performance. In conclusion, left motor dysfunction and smaller right SN volume are associated with poorer spatial memory

Emotional eating phenotype is associated with central dopamine D2 receptor binding independent of body mass index

PET studies have provided mixed evidence regarding central D2/D3 dopamine receptor binding and its relationship with obesity as measured by body mass index (BMI). Other aspects of obesity may be more tightly coupled to the dopaminergic system. We characterized obesity-associated behaviors and determined if these related to central D2 receptor (D2R) specific binding independent of BMI. Twenty-two obese and 17 normal-weight participants completed eating- and reward-related questionnaires and underwent PET scans using the D2R-selective and nondisplaceable radioligand (N-[(11)C]methyl)benperidol. Questionnaires were grouped by domain (eating related to emotion, eating related to reward, non-eating behavior motivated by reward or sensitivity to punishment). Normalized, summed scores for each domain were compared between obese and normal-weight groups and correlated with striatal and midbrain D2R binding. Compared to normal-weight individuals, the obese group self-reported higher rates of eating related to both emotion and reward (p < 0.001), greater sensitivity to punishment (p = 0.06), and lower non-food reward behavior (p < 0.01). Across normal-weight and obese participants, self-reported emotional eating and non-food reward behavior positively correlated with striatal (p < 0.05) and midbrain (p < 0.05) D2R binding, respectively. In conclusion, an emotional eating phenotype may reflect altered central D2R function better than other commonly used obesity-related measures such as BMI

Diffusion Tensor Imaging Of the Brain in Type 1 Diabetes

Individuals with Type 1 diabetes mellitus (T1DM) are required to carefully manage their insulin dosing, dietary intake, and activity levels in order to maintain optimal blood sugar levels. Over time, exposure to hyperglycaemia is known to cause significant damage to the peripheral nervous system, but its impact on the central nervous system has been less well studied. Researchers have begun to explore the cumulative impact of commonly experienced blood glucose fluctuations on brain structure and function in patient populations. To date, these studies have typically used magnetic resonance imaging to measure regional grey and white matter volumes across the brain. However, newer methods, such as diffusion tensor imaging (DTI) can measure the microstructural properties of white matter, which can be more sensitive to neurological effects than standard volumetric measures. Studies are beginning to use DTI to understand the impact of T1DM on white matter structure in the human brain. This work, its implications, future directions, and important caveats, are the focus of this review

Validation of the reference tissue model for estimation of dopaminergic D2-like receptor binding with [18F](N-methyl)benperidol in humans

PET measurements of dopaminergic D(2)-like receptors may provide important insights into disorders such as Parkinson's disease, schizophrenia, dystonia and Tourette's syndrome. The PET radioligand [(18) F] (N-Methyl)Benperidol ([(18)F]-NMB) has high affinity and selectivity for D(2)-like receptors and is not displaced by endogenous dopamine. The goal of this study is to evaluate use of a graphical method utilizing a reference tissue region for ([(18)F]-NMB PET analysis by comparisons to an explicit three-compartment tracer kinetic model and graphical method that use arterial blood measurements. We estimated binding potential (BP) in the caudate and putamen using all three methods in 16 humans and found that the three-compartment tracer kinetic method provided the highest BP estimates while the graphical method using a reference region yielded the lowest estimates (p<0.0001 by repeated measures ANOVA). However, the three methods yielded highly correlated BP estimates for the two regions of interest. We conclude that the graphical method using a reference region still provides a useful estimate of BP comparable to methods using arterial blood sampling, especially since the reference region method is less invasive and computationally more straightforward; thereby simplifying these measurements

[18F]FDOPA PET and clinical features in parkinsonism due to manganism

Manganese exposure reportedly causes a clinically and pathophysiologically distinct syndrome from idiopathic Parkinson\u27s disease (PD). We describe the clinical features and results of positron emission tomography with 6-[18F]fluorodopa ([18F]FDOPA PET) of a patient with parkinsonism occurring in the setting of elevated blood manganese. The patient developed parkinsonism associated with elevated serum manganese from hepatic dysfunction. [18F]FDOPA PET demonstrated relatively symmetric and severely reduced [18F]FDOPA levels in the posterior putamen compared to controls. The globus pallidum interna had increased signal on T1-weighted magnetic resonance imaging (MRI) images. We conclude that elevated manganese exposure may be associated with reduced striatal [18F]FDOPA uptake, and MRI may reveal selective abnormality within the internal segment of the pallidum. This case suggests that the clinical and pathophysiological features of manganese-associated parkinsonism may overlap with that of PD