Alpha-synuclein is the main constituent of intra-neuronal Lewy bodies, which are characteristic of Parkinson's disease, but aggregates are also found as axonal inclusions. Alpha-synuclein pathology is found together with beta-amyloid plaques and neurofibrillary tangles in Alzheimer's disease and other neurodegenerative disorders. In spite of the fact that the biological function of this synaptic protein is not known so far, there is an increasing body of evidence indicating an interaction with amyloid peptides, but also with tau-hyperphosphorylation. A high proportion of alpha-synuclein purified from Lewy bodies is phosphorylated on Ser129. There are still different opinions about the toxicity of the alpha-synuclein aggregates. Alpha-synuclein seems to influence different intracellular signaling pathways which are in direct relation to defense mechanisms against reactive oxygen species or apoptosis. It is obvious that overproduction of alpha-synuclein, but also different mutations, are inducing the formation of aggregates. Because of the possible link to neurodegeneration, different attempts have been made to counteract alpha-synuclein aggregation. An interesting approach is utilizing beta-synuclein, a biological factor, with an aminoacid sequence closely resembling that of alpha-synuclein. Proof of concept studies indicated that overexpression of beta-synuclein is able to counteract alpha-synuclein aggregation in a transgenic animal model, while also ameliorating functional deficits. As an alternative approach, the use of low molecular beta-synuclein N-terminal peptide derivatives has been considered. Several of these structures displayed clear neuroprotective activities in tissue culture models of neurodegeneration, including beta-amyloid toxicity. Therefore it has been speculated that these compounds might have a broad therapeutic efficacy in different neurodegenerative disorders. A proof of concept study in hAPP-transgenic animals resulted in a highly significant decrease in beta-amyloid plaque load, an increase in soluble beta-amyloid peptides and a decrease in insoluble forms. There was also significant improvement of cognitive deficits in this APP transgenic mouse model following intranasal but also peripheral treatment with three of these compounds. From this study it is concluded that the observed effects of the peptides derived from beta-synuclein N-terminus are depending on both, a direct interaction with aggregation of proteins, but also with stimulation of anti-apoptotic and anti-oxidative intracellular signaling pathways.
"Stiedl et al. (1999) reported that B6JOla and B6NCrl differed in their course of extinction of conditioned fear, with B6NCrl showing a slower decline of fear in response to a conditioned stimulus than B6JOla. In B6JOla from Harlan, Specht & Schoepfer (2001) found a spontaneous chromosomal deletion of the gene that encodes the presynaptic protein alpha-synuclein, which has been implicated in synaptic transmission and the etiology of a range of neurodegenerative disorders (Windisch et al. 2007), whereas the alpha-synuclein gene is present in B6NCrl mice and B6JCrl mice (Siegmund et al. 2005). This prompted Siegmund et al. (2005) to study whether this inter-substrain difference in alphasynuclein expression is involved in the different extinction of conditioned fear in B6 substrains, but no relationship was found. "
[Show abstract][Hide abstract] ABSTRACT: In rodents, the cholinomimetic convulsant pilocarpine is widely used to induce status epilepticus (SE), followed by hippocampal damage and spontaneous recurrent seizures, resembling temporal lobe epilepsy. This model has initially been described in rats, but is increasingly used in mice, including the C57BL/6 (B6) inbred strain. In the present study, we compared the effects of pilocarpine in three B6 substrains (B6JOla, B6NHsd and B6NCrl) that were previously reported to differ in several behavioral and genetic aspects. In B6JOla and B6NHsd, only a small percentage of mice developed SE independently of whether pilocarpine was administered at high bolus doses or with a ramping up dosing protocol, but mortality was high. The reverse was true in B6NCrl, in which a high percentage of mice developed SE, but mortality was much lower compared to the other substrains. However, in subsequent experiments with B6NCrl mice, striking differences in SE induction and mortality were found in sublines of this substrain coming from different barrier rooms of the same vendor. In B6NCrl from Barrier #8, administration of pilocarpine resulted in a high percentage of mice developing SE, but mortality was low, whereas the opposite was found in B6NCrl mice from four other barriers of the same vendor. The analysis of F1 mice from a cross of female Barrier 8 pilocarpine-susceptible mice with resistant male mice from another barrier (#9) revealed that F1 male mice were significantly more sensitive to pilocarpine than the resistant parental male mice whereas female F1 mice were not significantly different from resistant Barrier 9 females. These observations strongly indicate X-chromosome linked genetic variation as the cause of the observed phenotypic alterations. To our knowledge, this is the first report which demonstrates that not only the specific B6 substrain but also sublines derived from the same substrain may markedly differ in their response to convulsants such as pilocarpine. As the described differences have a genetic basis, they offer a unique opportunity to identify the genes and pathways involved and contribute to a better understanding of the underlying molecular mechanisms of seizure susceptibility.
[Show abstract][Hide abstract] ABSTRACT: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by oligodendrocytic cytoplasmic inclusions containing abnormally aggregated alpha-synuclein. This aggregation has been linked to the neurodegeneration observed in MSA. Current MSA treatments are aimed at controlling symptoms rather than tackling the underlying cause of neurodegeneration. This study investigates the ability of the antibiotic rifampicin to reduce alpha-synuclein aggregation and the associated neurodegeneration in a transgenic mouse model of MSA. We report a reduction in monomeric and oligomeric alpha-synuclein and a reduction in phosphorylated alpha-synuclein (S129) upon rifampicin treatment. This reduction in alpha-synuclein aggregation was accompanied by reduced neurodegeneration. On the basis of its anti-aggregenic properties, we conclude that rifampicin may have therapeutic potential for MSA.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.