Analysis of striatal transcriptome in mice overexpressing human wild-type alpha-synuclein supports synaptic dysfunction and suggests mechanisms of neuroprotection for striatal neurons

Abstract Background Alpha synuclein (SNCA) has been linked to neurodegenerative diseases (synucleinopathies) that include Parkinson's disease (PD). Although the primary neurodegeneration in PD involves nigrostriatal dopaminergic neurons, more extensive yet regionally selective neurodegeneration is observed in other synucleinopathies. Furthermore, SNCA is ubiquitously expressed in neurons and numerous neuronal systems are dysfunctional in PD. Therefore it is of interest to understand how overexpression of SNCA affects neuronal function in regions not directly targeted for neurodegeneration in PD. Results The present study investigated the consequences of SNCA overexpression on cellular processes and functions in the striatum of mice overexpressing wild-type, human SNCA under the Thy1 promoter (Thy1-aSyn mice) by transcriptome analysis. The analysis revealed alterations in multiple biological processes in the striatum of Thy1-aSyn mice, including synaptic plasticity, signaling, transcription, apoptosis, and neurogenesis. Conclusion The results support a key role for SNCA in synaptic function and revealed an apoptotic signature in Thy1-aSyn mice, which together with specific alterations of neuroprotective genes suggest the activation of adaptive compensatory mechanisms that may protect striatal neurons in conditions of neuronal overexpression of SNCA

Vocalization deficits in mice over-expressing alpha-synuclein, a model of pre-manifest Parkinson’s disease.

Communication and swallowing deficits are common in Parkinson’s disease (PD). Evidence indicates that voice and speech dysfunction manifest early, prior to motor deficits typically associated with striatal dopamine loss. Unlike deficits in the extremities, cranial sensorimotor deficits are refractory to standard dopamine-related pharmacological and surgical interventions, thus the mechanisms underlying vocal deficits are unclear. While neurotoxin models have provided some insight, they typically model nigrostriatal dopamine depletion and are therefore limited. Widespread alpha-synuclein (aSyn) pathology is common to familial and sporadic PD, and transgenic mouse models based on aSyn over-expression present a unique opportunity to explore vocalization deficits in relation to extra-striatal, non-dopaminergic pathologies. Specifically, mice over-expressing human wild-type aSyn under a broad neuronal promoter (Thy1-aSyn) present early, progressive motor and non-motor deficits starting at 2–3 months, followed by parkinsonism with dopamine loss at 14 months. We recorded ultrasonic vocalizations from Thy1-aSyn mice and wild-type (WT) controls at 2–3, 6–7 and 9 months. Thy1- aSyn mice demonstrated early, progressive vocalization deficits compared to WT. Duration and intensity of calls were significantly reduced and call profile was altered in the Thy1-aSyn mice, particularly at 2–3 months. Call rate trended towards a more drastic decrease with age in the Thy1-aSyn mice compared to WT. Alpha-synuclein pathology is present in the periaqueductal gray and may underlie the manifestation of vocalization deficits. These results indicate that aSyn over-expression can induce vocalization deficits at an early age in mice and provides a new model for studying the mechanisms underlying cranial sensorimotor deficits and treatment interventions for PD

Pros and cons of a prion-like pathogenesis in Parkinson's disease

Background: Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder which affects widespread areas of the brainstem, basal ganglia and cerebral cortex. A number of proteins are known to accumulate in parkinsonian brains including ubiquitin and alpha-synuclein. Prion diseases are sporadic, genetic or infectious disorders with various clinical and histopathological features caused by prion proteins as infectious proteinaceous particles transmitting a misfolded protein configuration through brain tissue. The most important form is Creutzfeldt-Jakob disease which is associated with a self-propagating pathological precursor form of the prion protein that is physiologically widely distributed in the central nervous system. Discussion: It has recently been found that alpha-synuclein may behave similarly to the prion precursor and propagate between cells. The post-mortem proof of alpha-synuclein containing Lewy bodies in embryonic dopamine cells transplants in PD patient suggests that the misfolded protein might be transmitted from the diseased host to donor neurons reminiscent of prion behavior. The involvement of the basal ganglia and brainstem in the degenerative process are other congruencies between Parkinson's and Creutzfeldt-Jakob disease. However, a number of issues advise caution before categorizing Parkinson's disease as a prion disorder, because clinical appearance, brain imaging, cerebrospinal fluid and neuropathological findings exhibit fundamental differences between both disease entities. Most of all, infectiousness, a crucial hallmark of prion diseases, has never been observed in PD so far. Moreover, the cellular propagation of the prion protein has not been clearly defined and it is, therefore, difficult to assess the molecular similarities between the two disease entities. Summary: At the current state of knowledge, the molecular pathways of transmissible pathogenic proteins are not yet fully understood. Their exact involvement in the pathophysiology of prion disorders and neurodegenerative diseases has to be further investigated in order to elucidate a possible overlap between both disease categories that are currently regarded as distinct entities

Stepped Care for Maternal Mental Health: A Case Study of the Perinatal Mental Health Project in South Africa

As one article in a series on Global Mental Health Practice, Simone Honikman and colleagues from South Africa provide a case study of the Perinatal Mental Health Project, which delivered mental health care to pregnant women in a collaborative, step-wise manner, making use of existing resources in primary care

Context Dependent Neuroprotective Properties of Prion Protein (Prp)

Although it has been known for more than twenty years that an aberrant conformation of the prion protein (PrP) is the causative agent in prion diseases, the role of PrP in normal biology is undetermined. Numerous studies have suggested a protective function for PrP, including protection from ischemic and excitotoxic lesions and several apoptotic insults. On the other hand, many observations have suggested the contrary, linking changes in PrP localization or domain structure—independent of infectious prion conformation—to severe neuronal damage. Surprisingly, a recent report suggests that PrP is a receptor for toxic oligomeric species of a-β, a pathogenic fragment of the amyloid precursor protein, and likely contributes to disease pathogenesis of Alzheimer’s disease. We sought to access the role of PrP in diverse neurological disorders. First, we confirmed that PrP confers protection against ischemic damage using an acute stroke model, a well characterized association. After ischemic insult, PrP knockouts had dramatically increased infarct volumes and decreased behavioral performance compared to controls. To examine the potential of PrP’s neuroprotective or neurotoxic properties in the context of other pathologies, we deleted PrP from several transgenic models of neurodegenerative disease. Deletion of PrP did not substantially alter the disease phenotypes of mouse models of Parkinson’s disease or tauopathy. Deletion of PrP in one of two Huntington’s disease models tested, R6/2, modestly slowed motor deterioration as measured on an accelerating rotarod but otherwise did not alter other major features of the disease. Finally, transgenic overexpression of PrP did not exacerbate the Huntington’s motor phenotype. These results suggest that PrP has a context-dependent neuroprotective function and does not broadly contribute to the disease models tested herein.Ellison Medical FoundationWhitaker Health Sciences Fund Fellowshi

Parkin-deficient Mice Exhibit Nigrostriatal Deficits but not Loss of Dopaminergic Neurons

Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson's disease. To investigate the pathogenic mechanism by which loss of parkin function causes Parkinson's disease, we generated a mouse model bearing a germline disruption in parkin. Parkin-/- mice are viable and exhibit grossly normal brain morphology. Quantitative in vivo microdialysis revealed an increase in extracellular dopamine concentration in the striatum of parkin-/- mice. Intracellular recordings of medium-sized striatal spiny neurons showed that greater currents are required to induce synaptic responses, suggesting a reduction in synaptic excitability in the absence of parkin. Furthermore, parkin-/- mice exhibit deficits in behavioral paradigms sensitive to dysfunction of the nigrostriatal pathway. The number of dopaminergic neurons in the substantia nigra of parkin-/- mice, however, is normal up to the age of 24 months, in contrast to the substantial loss of nigral neurons characteristic of Parkinson's disease. Steady-state levels of CDCrel-1, synphilin-1, and α-synuclein, which were identified previously as substrates of the E3 ubiquitin ligase activity of parkin, are unaltered in parkin-/- brains. Together these findings provide the first evidence for a novel role of parkin in dopamine regulation and nigrostriatal function, and a non-essential role of parkin in the survival of nigral neurons in mice

Phenotype onset in Huntington's disease knock-in mice is correlated with the incomplete splicing of the mutant huntingtin gene

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG repeat within the huntingtin (HTT) gene. The Q140 and HdhQ150 knock‐in HD mouse models were generated such that HdhQ150 mice have an expanded CAG repeat inserted into the mouse Htt gene, whereas in the Q140s, mouse exon 1 Htt was replaced with a mutated version of human exon 1. By standardizing mouse strain background, breeding to homozygosity and employing sensitive behavioral tests, we demonstrate that the onset of behavioral phenotypes occurs earlier in the Q140 than the HdhQ150 knock‐in mouse models and that huntingtin (HTT) aggregation appears earlier in the striata of Q140 mice. We have previously found that the incomplete splicing of mutant HTT from exon 1 to exon 2 results in the production of a small polyadenylated transcript that encodes the highly pathogenic mutant HTT exon 1 protein. In this report, we have identified a functional consequence of the sequence differences between these two models at the RNA level, in that the level of incomplete splicing, and of the mutant exon 1 HTT protein, are greater in the brains of Q140 mice. While differences in the human and mouse exon 1 HTT proteins (e.g., proline rich sequences) could also contribute to the phenotypic differences, our data indicate that the incomplete splicing of HTT and approaches to lower the levels of the exon 1 HTT transcript should be pursued as therapeutic targets

Sources and cycling of dissolved and particulate organic radiocarbon in the northwest Atlantic continental margin

Continental shelves and slopes are productive and dynamic ocean margin systems that also regulate the fluxes of terrestrial, riverine, and estuarine materials between the continents and oceans. In order to evaluate the ages, potential sources, and transformations of organic matter in an ocean margin system, we measured the radiocarbon (Delta (14)C and delta (13)C distributions of total dissolved organic carbon (DOC), suspended particulate organic carbon (POC), and dissolved inorganic carbon (DIC) in waters of the Middle Atlantic Bight (MAB) continental shelf and slope in April-May 1994. The Delta (14)C of DOC was greatest (as high as -39 parts per thousand) in surface waters of the shelf, decreasing rapidly offshore and with depth, even in relatively shallow (25-50 in depth) shelf waters. The lowest Delta (14)C-DOC values were observed in deep slope waters, where they were significantly lower than values measured previously for the deep Sargasso Sea. There was a strong inverse relationship between Delta (14)C-DOC and delta (-13)C-DOC in all shelf and surface slope waters of the MAB, which is likely attributable to varying contributions of young, (14)C-enriched organic matter of terrestrial and/or riverine origin. The more highly (14)C-depleted DOC in deep : slope waters (as low as -442 parts per thousand) generally had a correspondingly lower delta (13)C (as low as -22.3 parts per thousand) component. However, this must originate from relic terrestrial material either in the MAB itself or be discharged to the MAB from rivers and estuaries. The isotopic signatures of POC were clearly differentiable from DOC and indicate that this pool also contained a broad range of both old and young material of terrestrial (delta (13)C as low as -24.9 parts per thousand) and marine (delta (13)C as high as -19.9 parts per thousand) origin throughout the MAB shelf and slope. The highest Delta (14)C-POC values (up to 78 parts per thousand) were observed in shallow shelf waters of the southern MAR Conversely, the lowest Delta (14)C-POC values (as low as -394 parts per thousand) were found in MAB deep slope waters and were also significantly more depleted in (14)C than POC from the central north Atlantic (Sargasso Sea). A multiple-source isotopic mass balance model employing both (14)C and (13)C was used to evaluate the relative contributions of both young and old terrigenous versus marine organic matter to DOC and POC in the MAR The results indicate that shelf and slope DOC is comprised of an old marine fraction (represented by offshore Sargasso Sea material) and either a young terrestrial/riverine/estuarine (TRE) component (in shelf and shallow slope waters) or a relic TRE component (in deep and some shallow slope waters). In contrast, suspended POC from the MAB appears to originate predominantly from a mixture of recent MAB primary production and an old, TRE component, similar to that observed in one of the major subestuaries of the Chesapeake Bay. These results suggest that both young and old sources of terrestrial and riverine organic matter can comprise a significant fraction of the DOC and POC in ocean margins. Preliminary calculations indicate that the export of this compositionally unique DOC and suspended POC may be significant terms in the organic carbon budgets of the MAB and other margin systems

Postsynaptic nigrostriatal dopamine receptors and their role in movement regulation

The article presents the hypothesis that nigrostriatal dopamine may regulate movement by modulation of tone and contraction in skeletal muscles through a concentration-dependent influence on the postsynaptic D1 and D2 receptors on the follow manner: nigrostriatal axons innervate both receptor types within the striatal locus somatotopically responsible for motor control in agonist/antagonist muscle pair around a given joint. D1 receptors interact with lower and D2 receptors with higher dopamine concentrations. Synaptic dopamine concentration increases immediately before movement starts. We hypothesize that increasing dopamine concentrations stimulate first the D1 receptors and reduce muscle tone in the antagonist muscle and than stimulate D2 receptors and induce contraction in the agonist muscle. The preceded muscle tone reduction in the antagonist muscle eases the efficient contraction of the agonist. Our hypothesis is applicable for an explanation of physiological movement regulation, different forms of movement pathology and therapeutic drug effects. Further, this hypothesis provides a theoretical basis for experimental investigation of dopaminergic motor control and development of new strategies for treatment of movement disorders