Altered expression of genes involved in ganglioside biosynthesis in substantia nigra neurons in Parkinson\u27s disease.

Reduced expression of GM1 and other major brain gangliosides GD1a, GD1b and GT1b have been reported in Parkinson\u27s disease (PD) brain. Mechanisms underlying these changes are unclear but may be due to a deficit in the ganglioside biosynthetic process. The present study examined the extent to which deficits in gene expression of key biosynthetic enzymes involved in synthesis of GM1 and GD1b (B3galt4) and GD1a and GT1b (St3gal2) exist in neuromelanin-containing neurons in the PD substantia nigra (SN). In situ hybridization histochemistry was used to examine gene expression of B3GALT4 and ST3GAL2 in neuromelanin-containing neurons in the SN in 8 normal controls (61-92 yrs.) and 7 PD subjects (77-95 yrs). There was a significant decrease in both B3GALT4 and ST3GAL2 gene expression in residual neuromelanin-containing cells in the SN of PD patients compared to age-matched neurologically normal controls. These changes appeared to be cell-type specific as abundant B3GALT4 and ST3GAL2 gene expression was observed in non-neuromelanin containing neurons located outside of the SN in the PD brain. These data show that residual neuromelanin-containing neurons in the PD SN have decreased expression of the ganglioside biosynthetic genes B3GALT4 and ST3GAL2, consistent with previous reports of decreased levels of gangliosides GM1, GD1a, GD1b and GT1b in the PD SN. These changes may increase the vulnerability of these neurons to degeneration in response to a variety of potential stressors

Different Behavioral Experiences Produce Distinctive Parallel Changes in, and Correlate With, Frontal Cortex and Hippocampal Global Post-translational Histone Levels.

While it is clear that behavioral experience modulates epigenetic profiles, it is less evident how the nature of that experience influences outcomes and whether epigenetic/genetic biomarkers could be extracted to classify different types of behavioral experience. To begin to address this question, male and female mice were subjected to either a Fixed Interval (FI) schedule of food reward, or a single episode of forced swim followed by restraint stress, or no explicit behavioral experience after which global expression levels of two activating (H3K9ac and H3K4me3) and two repressive (H3K9me2 and H3k27me3) post-translational histone modifications (PTHMs), were measured in hippocampus (HIPP) and frontal cortex (FC). The specific nature of the behavioral experience differentiated profiles of PTHMs in a sex- and brain region-dependent manner, with all 4 PTHMs changing in parallel in response to different behavioral experiences. These different behavioral experiences also modified the pattern of correlations of PTHMs both within and across FC and HIPP. Unexpectedly, highly robust correlations were found between global PTHM levels and behavioral performances, suggesting that global PTHMs may provide a higher-order pattern recognition function. Further efforts are needed to determine the generality of such findings and what characteristics of behavioral experience are critical for modulating PTHM responses

Developmental Lead and/or Prenatal Stress Exposures Followed by Different Types of Behavioral Experience Result in the Divergence of Brain Epigenetic Profiles in a Sex, Brain Region, and Time-Dependent Manner: Implications for Neurotoxicology.

Over a lifetime, early developmental exposures to neurocognitive risk factors, such as lead (Pb) exposures and prenatal stress (PS), will be followed by multiple varied behavioral experiences. Pb, PS and behavioral experience can each influence brain epigenetic profiles. Our recent studies show a greater level of complexity, however, as all three factors interact within each sex to generate differential adult variation in global post-translational histone modifications (PTHMs), which may result in fundamentally different consequences for life-long learning and behavioral function. We have reported that PTHM profiles differ by sex, brain region and time point of measurement following developmental exposures to Pb±PS, resulting in different profiles for each unique combination of these parameters. Imposing differing behavioral experience following developmental Pb±PS results in additional divergence of PTHM profiles, again in a sex, brain region and time-dependent manner, further increasing complexity. Such findings underscore the need to link highly localized and variable epigenetic changes along single genes to the highly-integrated brain functional connectome that is ultimately responsible for governing behavioral function. Here we advance the idea that increased understanding may be achieved through iterative reductionist and holistic approaches. Implications for experimental design of animal studies of developmental exposures to neurotoxicants include the necessity of a \u27no behavioral experience\u27 group, given that epigenetic changes in response to behavioral testing can confound effects of the neurotoxicant itself. They also suggest the potential utility of the inclusion of salient behavioral experiences as a potential effect modifier in epidemiological studies

Relationship between Motor Symptoms, Cognition, and Demographic Characteristics in Treated Mild/Moderate Parkinson\u27s Disease.

BACKGROUND: Although Parkinson\u27s disease (PD) is a progressive neurodegenerative disorder characterized primarily by motor symptoms, PD patients, at all stages of the disease, can experience cognitive dysfunction. However, the relationships between cognitive and motor symptoms and specific demographic characteristics are not well defined, particularly for patients who have progressed to requiring dopaminergic medication. OBJECTIVE: To examine relationships between motor and cognitive symptoms and various demographic factors in mild to moderate, PD patients requiring anti-PD medication. METHODS: Cognitive function was assessed in 94 subjects with a variety of neuropsychological tests during baseline evaluations as part of an experimental treatment study. Data were analyzed in relation to Unified Parkinson\u27s Disease Rating Scale motor scores and demographic variables. RESULTS: Of the UPDRS subscores analyzed, posture/balance/gait was associated with the highest number of adverse cognitive outcomes followed by speech/facial expression, bradykinesia, and rigidity. No associations were detected between any of the cognitive performance measures and tremor. Motor functioning assessed in the off condition correlated primarily with disease duration; neuropsychological performance in general was primarily related to age. CONCLUSION: In PD patients who have advanced to requiring anti-PD therapies, there are salient associations between axial signs and cognitive performance and in particular, with different aspects of visuospatial function suggesting involvement of similar circuits in these functions. Associations between executive functions and bradykinesia also suggest involvement similar circuits in these functions

Relationship between Motor Symptoms, Cognition, and Demographic Characteristics in Treated Mild/Moderate Parkinson\u27s Disease.

BACKGROUND: Although Parkinson\u27s disease (PD) is a progressive neurodegenerative disorder characterized primarily by motor symptoms, PD patients, at all stages of the disease, can experience cognitive dysfunction. However, the relationships between cognitive and motor symptoms and specific demographic characteristics are not well defined, particularly for patients who have progressed to requiring dopaminergic medication. OBJECTIVE: To examine relationships between motor and cognitive symptoms and various demographic factors in mild to moderate, PD patients requiring anti-PD medication. METHODS: Cognitive function was assessed in 94 subjects with a variety of neuropsychological tests during baseline evaluations as part of an experimental treatment study. Data were analyzed in relation to Unified Parkinson\u27s Disease Rating Scale motor scores and demographic variables. RESULTS: Of the UPDRS subscores analyzed, posture/balance/gait was associated with the highest number of adverse cognitive outcomes followed by speech/facial expression, bradykinesia, and rigidity. No associations were detected between any of the cognitive performance measures and tremor. Motor functioning assessed in the off condition correlated primarily with disease duration; neuropsychological performance in general was primarily related to age. CONCLUSION: In PD patients who have advanced to requiring anti-PD therapies, there are salient associations between axial signs and cognitive performance and in particular, with different aspects of visuospatial function suggesting involvement of similar circuits in these functions. Associations between executive functions and bradykinesia also suggest involvement similar circuits in these functions

Neurotoxicity and Outcomes from Developmental Lead Exposure: Persistent or Permanent?

Background: Childhood lead poisoning remains an important public health issue in the United States, as well as elsewhere in the world. Although primary prevention is a major goal and it is critically important to keep children from getting poisoned, it is also important to explore ways to reduce the neurotoxic effects of lead in those children already poisoned. Whether lead-induced neurotoxicity and its related adverse outcomes are viewed as “permanent” or “persistent” may influence the way in which potential remediation efforts are considered for improving outcomes from childhood lead poisoning. Objectives: The objective of this commentary was to discuss the ideas of permanence and persistence in relation to the direct neurotoxic effects of lead on the brain and the resulting adverse outcomes from these effects. Recent new insights regarding potential mitigation of lead-induced neurotoxic effects on brain and behavior are considered along with clinical information on neurorehabilitation to suggest potential strategies for improving cognitive/behavioral outcomes in lead-poisoned children. Discussion: The distinction between permanent and persistent in regard to lead-induced neurotoxicity and its resulting outcomes may have broad implications for public health policies in response to the problem of childhood lead exposure. The term permanent implies that the damage is irreversible with little chance of improvement. However, there is evidence that at least some of the adverse cognitive/behavioral outcomes from lead exposure are persistent rather than permanent and potentially amenable, under the appropriate circumstances, to some level of mitigation. This author recommends that clinical, interventional research efforts be devoted to exploring optimal neurorehabilitative and enrichment conditions to stimulate plasticity and enhance functioning to determine the extent to which promising results from preclinical studies of lead-induced brain damage and the mitigation of these effects can be successfully translated to humans

GM1 Ganglioside as a Disease-Modifying Therapeutic for Parkinson’s Disease: A Multi-Functional Glycosphingolipid That Targets Multiple Parkinson’s Disease-Relevant Pathogenic Mechanisms

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting millions of patients worldwide. Many therapeutics are available for treating PD symptoms but there is no disease-modifying therapeutic that has been unequivocally shown to slow or stop the progression of the disease. There are several factors contributing to the failure of many putative disease-modifying agents in clinical trials and these include the choice of patients and clinical trial designs for disease modification trials. Perhaps more important, however, is the choice of therapeutic, which for the most part, has not taken into account the multiple and complex pathogenic mechanisms and processes involved in PD. This paper discusses some of the factors contributing to the lack of success in PD disease-modification trials, which have mostly investigated therapeutics with a singular mechanism of action directed at one of the many PD pathogenic processes, and suggests that an alternative strategy for success may be to employ multi-functional therapeutics that target multiple PD-relevant pathogenic mechanisms. Evidence is presented that the multi-functional glycosphingolipid GM1 ganglioside may be just such a therapeutic

GM1 Ganglioside Modifies α-Synuclein Toxicity and is Neuroprotective in a Rat α-Synuclein Model of Parkinson\u27s Disease.

While GM1 may interact with α-synuclein in vitro to inhibit aggregation, the ability of GM1 to protect against α-synuclein toxicity in vivo has not been investigated. We used targeted adeno-associated viral vector (AAV) overexpression of human mutant α-synuclein (A53T) in the rat substantia nigra (SN) to produce degeneration of SN dopamine neurons, loss of striatal dopamine levels, and behavioral impairment. Some animals received daily GM1 ganglioside administration for 6 weeks, beginning 24 hours after AAV-A53T administration or delayed start GM1 administration for 5 weeks beginning 3 weeks after AAV-A53T administration. Both types of GM1 administration protected against loss of SN dopamine neurons and striatal dopamine levels, reduced α-synuclein aggregation, and delayed start administration of GM1 reversed early appearing behavioral deficits. These results extend prior positive results in MPTP models, are consistent with the results of a small clinical study of GM1 in PD patients that showed slowing of symptom progression with chronic use, and argue for the continued refinement and development of GM1 as a potential disease modifying therapy for PD

Intraventricular Sialidase Administration Enhances GM1 Ganglioside Expression and Is Partially Neuroprotective in a Mouse Model of Parkinson\u27s Disease.

BACKGROUND: Preclinical and clinical studies have previously shown that systemic administration of GM1 ganglioside has neuroprotective and neurorestorative properties in Parkinson\u27s disease (PD) models and in PD patients. However, the clinical development of GM1 for PD has been hampered by its animal origin (GM1 used in previous studies was extracted from bovine brains), limited bioavailability, and limited blood brain barrier penetrance following systemic administration. OBJECTIVE: To assess an alternative therapeutic approach to systemic administration of brain-derived GM1 to enhance GM1 levels in the brain via enzymatic conversion of polysialogangliosides into GM1 and to assess the neuroprotective potential of this approach. METHODS: We used sialidase from Vibrio cholerae (VCS) to convert GD1a, GD1b and GT1b gangliosides to GM1. VCS was infused by osmotic minipump into the dorsal third ventricle in mice over a 4-week period. After the first week of infusion, animals received MPTP injections (20 mg/kg, s.c., twice daily, 4 hours apart, for 5 consecutive days) and were euthanized 2 weeks after the last injection. RESULTS: VCS infusion resulted in the expected change in ganglioside expression with a significant increase in GM1 levels. VCS-treated animals showed significant sparing of striatal dopamine (DA) levels and substantia nigra DA neurons following MPTP administration, with the extent of sparing of DA neurons similar to that achieved with systemic GM1 administration. CONCLUSION: The results suggest that enzymatic conversion of polysialogangliosides to GM1 may be a viable treatment strategy for increasing GM1 levels in the brain and exerting a neuroprotective effect on the damaged nigrostriatal DA system

Effects of chronic manganese exposure on attention and working memory in non-human primates.

Manganese (Mn) is essential for a variety of physiological processes, but at elevated levels, can be neurotoxic. While cognitive dysfunction has been recently appreciated to occur as a result of chronic Mn exposures, it is still unclear as to which cognitive domains are most susceptible to disruption by Mn exposure. We previously described early appearing Mn-induced changes in performance on a paired associate learning task in monkeys chronically exposed to Mn and suggested that performance of this task might be a sensitive tool for detecting cognitive dysfunction resulting from Mn exposure. As chronic Mn exposure has been suggested to be associated with attention, working memory and executive function deficits, the present study was conducted to assess the extent to which detrimental effects of chronic Mn exposure could be detected using tasks specifically designed to preferentially assess attention, working memory, and executive function. Six cynomolgus monkeys received Mn exposure over an approximate 12 month period and three served as control animals. All animals were trained to perform a self-ordered spatial search (SOSS) task and a five choice serial reaction time (5-CSRT) task. Deficits in performance of the SOSS task began to appear by the fourth month of Mn exposure but only became consistently significantly impaired beginning at the ninth month of Mn exposure. Performance on the 5-CSRT became significantly affected by the third month of Mn exposure. These data suggest that in addition to the paired associate learning task, cognitive processing speed (as measured by the 5-CSRT) may be a sensitive measure of Mn toxicity and that brain circuits involved in performance of the SOSS task may be somewhat less sensitive to disruption by chronic Mn exposure