In the present study, we analyzed the uptake of radiolabeled dopamine by intact synaptosomes and purified synaptic vesicles isolated from the dorsal striatum of mice with constitutive inactivation of all three synuclein-coding genes and wild-type mice. Synuclein deficiency substantially compromised the uptake of this neurotransmitter by synaptic vesicles but had no effect on synaptosomal dopamine uptake.

Провели сравнительный анализ захвата радиоактивно меченого дофамина интактными синаптосомами и очищенными синаптическими везикулами, выделенными из дорзального стриатума мышеи с полной инактивацией генов, кодирующих все три синуклеина, и мышеи дикого типа. Отсутствие синуклеинов привело к существенному снижению эффективности захвата этого нейромедиатора синаптическими везикулами, но не повлияло на захват дофамина синаптосомами.

The purposeThis study investigated the role of alpha-synuclein in the development of dopaminergic neurons.MethodsIn this study a new SNCA knockout mouse line has been used to model the deficiency of alpha-synuclein function. In the knockout and control mice the dynamics of the formation of two distinct populations of dopaminergic neurons differently affected in patients with PD was studied by the comparative morphometric analysis.ResultsHere, we revealed a prominent modulating effect of alpha-synuclein on the developing DA neurons in substantia nigra (SN) which is the most affected region in PD patients. Yet, alpha-synuclein had no effect on the formation of DA neurons in ventral tegmental area which is much less susceptible to degeneration in PD patients.ConclusionThe new line of knockout mice is a convenient model for studying pathophysiologic aspects of selective impairment of DA neurons.

Alpha-synuclein is a presynaptic protein of vertebrates that belongs to the family of synucleins. Normal functions of synucleins remain unknown. Alpha-synuclein is one of the causative factors of the familial and idiopathic forms of Parkinson’s disease (PD). The progressive loss of dopaminergic (DA) neurons is characteristic of PD and the most severe damage occurs in the substantia nigra (SN). This leads to an erraticism of the synthesis and synaptic secretion of the neurotransmitters, subsequently resulting in the loss of the connections between brain areas. This work shows that alpha-synuclein is directly involved in the formation of the mature DA neurons of the midbrain at different stages of the ontogenesis and these findings are consistent with data obtained in other studies. Thus, alpha-synuclein may have a varying modulating effect on the growth dynamics and the fate of populations of DA neurons.

UNLABELLED:BACKGROUND AND ОBJECTIVE: Loss of conformation and function of sufficient number of proteins with high aggregation capacity plays an important role in the pathogenesis of many neurodegenerative disorders (NDD). Due to a recent discovery of new array of proteins with the capacity to form aggregates of nonamyloid type, new NDD models as well as a new level of understanding in vivo models which are already exist is needed. DNA/RN A binding proteins - FUS and TDP-43 play a crucial role in the pathogenesis of some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The objective of the study was to develop a new ALS transgenic model.MATERIAL AND METHODS:In cell culture experiments, we studied mutant FUS proteins capable to form intracellular deposits morphologically similar to those observed in the autopsy material of ALS patients.RESULTS AND CONCLUSION:We created a transgenic mice line, in which a pathogenic form of human FUS protein was expressed in the nervous system. That led to the aggregation of FUS protein in spinal cord and motor neurons with the following degeneration and development of a phenotype, similar to the human ALS disease phenotype, in young grown-up animals. This neurodegenerative phenotype corresponds to a great number of clinical manifestations of human ALS and is an adequate transgenic model of the disease.

Создана и охарактеризована новая линия мышей с повышенным синтезом белка гамма-синуклеина в тканях нервной системы на фоне генетического нокаута CSPα, являющимся ко-шаперонным белком синапсов. Ранее было показано, что при скрещивании линии мышей с сверхпродукцией альфа-синуклеина с CSPα нокаутами происходит восстановление фенотипа благодаря участию альфа-синуклеина в синаптической передаче. Поскольку альфа- и гамма-синуклеин структурно похожи, вероятно, что скрещивание CSPα нокаутов с линией мышей со сверхпродукцией гамма-синуклеин даст схожие результаты. В результате было показано, что гамма-синуклеин присутствует в больших количествах в синаптических окончаниях у полученных мышей, однако реверсия фенотипа CSPα нокаутных мышей не происходит, что указывает на отличную от альфа-синуклеина функцию в синапсах. Несмотря на структурное сходство альфа- и гамма-синуклеина, их функции в пресинаптических окончаниях разделены и не дублируются.

In the present study we have used a transgenic mouse line overexpressing an amyloidogenic protein, gamma-synuclein, in the nervous system to address the effect of dimebon on proteinopathy progression. Chronic dimebon administration increased lifespan in these transgenic mice, furthermore, using histological and biochemical approaches we have demonstrated that dimebon reduced the number of amyloid inclusions in the spinal cord of transgenic animals and decreased the content of ubiquitinated proteins in the detergent-insoluble fraction of the spinal cord. These effects are likely to occur at the level of aggregated protein species, since transgene expression remained unaltered during dimebon administration. Thus, pathological protein aggregation serves as one of dimebon targets in neurodegeneration.