Reduced expression of GM1 and other major brain gangliosides GD1a, GD1b and GT1b have been reported in Parkinson's 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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
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. https://doi.org/10.1289/EHP12371.
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CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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.
Although Parkinson's 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.
To examine relationships between motor and cognitive symptoms and various demographic factors in mild to moderate, PD patients requiring anti-PD medication.
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's Disease Rating Scale motor scores and demographic variables.
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.
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Impairment in various aspects of cognition is recognized as an important non-motor symptom of Parkinson's disease (PD). Mild cognitive impairment in PD (PD-MCI) is common in non-demented PD patients ...and is often associated with severity of motor symptoms, disease duration and increasing age. Further, PD-MCI can have a significant negative effect on performance of daily life activities and may be a harbinger of development of PD dementia. Thus, there is significant interest in developing therapeutic strategies to ameliorate cognitive deficits in PD and improve cognitive functioning of PD patients. However, due to significant questions that remain regarding the pathophysiology of cognitive dysfunction in PD, remediation of cognitive dysfunction in PD has proven difficult. In this paper, we will focus on PD-MCI and will review some of the current therapeutic approaches being taken to try to improve cognitive functioning in patients with PD-MCI.
This article is part of the Special Issue on ‘New therapeutic approaches to Parkinson’s disease'.
•Cognitive dysfunction is an important non-motor symptom of Parkinson's disease.•PD-MCI is common but has proven difficult to treat.•Current therapeutic approaches to improve cognition in PD are discussed.
The precise mechanisms initiating and perpetuating the cellular degeneration in Parkinson's disease (PD) remain unclear. There is decreased expression of the main brain gangliosides, and GM1 ...ganglioside in particular, in the PD brain along with decreased expression of the genes coding for the glycosyltranferase and the sialyltransferase responsible for the synthesis of these brain gangliosides. However, potentially important pathogenic mechanisms contributing to the neurodegeneration in PD may also include altered levels of expression of genes involved in glycosylation, sialylation and sphingolipid synthesis and metabolism. Although various studies have described pathological lipid and glycolipid changes in PD brain, there have been limited studies of expression of glycobiology-related genes in PD brain. The current study was performed as an initial attempt to gain new information regarding potential changes in glycoprotein and glycolipid-related genes in PD by investigating the gene expression status for select glycosyltransferases, sialyltransferases, sialidases, sphingosine kinases, and lysosomal enzymes in the substantia nigra and putamen from patients with PD and neurologically normal controls. Results showed altered expression of glycosyltransferase genes (
and
1) potentially involved in microglial activation and neuroinflammation, sphingosine-1-phosphate (S1P) modulators (
,
, and
) involved in sphingolipid synthesis and metabolism, polysialyltransferase genes (
and
) that encode enzymes responsible for polysialic acid (polySia) biosynthesis, and the sialidase
, expression of which has been linked to the clearance of storage materials from lysosomes. The data presented here underscore the complexity of the glycolipid/sphingolipid dysregulation in the PD brain and continued and expanded study of these processes may not only provide a greater understanding of the complex roles of aberrant glycosylation sialylation, and sphingolipid synthesis/metabolism in the pathophysiology of PD but may identify potential druggable targets for PD therapeutics.
Reduced levels of brain gangliosides GD1a, GD1b, GT1b and to a lesser extent GM1 have been found in substantia nigra (SN) from Parkinson's disease (PD) patients, along with decreased gene expression ...for key enzymes (B3Galt4, St3gal2) involved in synthesis of these gangliosides. Based on these observations, the present study examined the extent to which decreased expression of B3GALT4 mRNA and resulting decreased levels of GM1 ganglioside in dopaminergic cells may increase the vulnerability of these cells to degeneration in response to a neurotoxicant exposure that under normal circumstances would not result in neurodegeneration. Differentiated SK-N-SH cells were treated with B3GALT4 siRNA to significantly reduce B3GALT4 mRNA expression and decrease GM1 levels. Exposure of these cells to a low concentration (10 μM) of the neurotoxin MPP+ that previously produced no toxicity resulted in approximately 50% cell loss after B3GALT4 siRNA treatment. This was a similar a degree of cell loss observed with 100 μM MPP+ in normal, differentiated SK-N-SH cells. Addition of GM1 to the culture medium after siRNA treatment was able to significantly protect cells from enhanced MPP+ toxicity. These data suggest that decreased B3GALT4 and GM1 expression can increase cell vulnerability to potentially toxic stressors and that such mechanisms may contribute to dopaminergic neurodegeneration in PD.
•B3GALT4 siRNA significantly reduced B3GALT4 mRNA expression.•B3GALT4 siRNA significantly decreased GM1 levels.•B3GALT4 siRNA enhanced toxic response to low level MPP+.•Decreased B3GALT4 and GM1 expression increases cell vulnerability to toxic stressors.
Preclinical and clinical studies have previously shown that systemic administration of GM1 ganglioside has neuroprotective and neurorestorative properties in Parkinson's 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.
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.
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.
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.
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.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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