Development Of Motor Disorders Research Articles

PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats

Epidemiological and animal studies indicate that pre-existing diabetes increases the risk of Parkinson's disease (PD). However, the mechanisms underlying this association remain unclear. In the present study, we found that high glucose (HG) levels in the cerebrospinal fluid (CSF) of diabetic rats might enhance the effect of a subthreshold dose of the neurotoxin 6-hydroxydopamine (6-OHDA) on the development of motor disorders, and the damage to the nigrostriatal dopaminergic neuronal pathway. In vitro, HG promoted the 6-OHDA-induced apoptosis in PC12 cells differentiated to neurons with nerve growth factor (NGF) (NGF-PC12). Metabolomics showed that HG promoted hyperglycolysis in neurons and impaired tricarboxylic acid cycle (TCA cycle) activity, which was closely related to abnormal mitochondrial fusion, thus resulting in mitochondrial loss. Interestingly, HG-induced upregulation of pyruvate kinase M2 (PKM2) combined with 6-OHDA exposure not only mediated glycolysis but also promoted abnormal mitochondrial fusion by upregulating the expression of MFN2 in NGF-PC12 cells. In addition, we found that PKM2 knockdown rescued the abnormal mitochondrial fusion and cell apoptosis induced by HG+6-OHDA. Furthermore, we found that shikonin (SK), an inhibitor of PKM2, restored the mitochondrial number, promoted TCA cycle activity, reversed hyperglycolysis, enhanced the tolerance of cultured neurons to 6-OHDA, and reduced the risk of PD in diabetic rats. Overall, our results indicate that diabetes promotes hyperglycolysis and abnormal mitochondrial fusion in neurons through the upregulation of PKM2, leading to an increase in the vulnerability of dopaminergic neurons to 6-OHDA. Thus, the inhibition of PKM2 and restoration of mitochondrial metabolic homeostasis/pathways may prevent the occurrence and development of diabetic PD.

Early diagnostics of motor disorders in children: an interdisciplinary approach

Assessment of motor development is an important part of the study of the neuropsychic development of children, which is carried out by a pediatrician during preventive examinations. To identify the causes of motor disorders, in addition to studying the anamnesis, it is necessary to conduct a physical examination of the child with the appointment of additional research methods. It is important to remember that developmental delay does not always indicate the presence of any disease but requires dynamic monitoring. However, if they progress, then these patients are more likely to be diagnosed with specific neuromuscular disorders. In this case, the pediatrician should pay attention to the neurological status of the child, assess visual acuity and hearing. At the same time, one should not forget that motor disorders are often combined with a general developmental delay (mental retardation) of the child. Fasciculation of the tongue, loss of motor skills, organomegaly, coarsening of facial features, increased levels of creatine phosphokinase (more than 3 times higher than normal), respiratory failure, in the presence of general weakness, a sharp deterioration in the child’s condition, accompanied by lethargy, vomiting, development of convulsive syndrome, disorders detected on MRI of the brain, are alarming symptoms that require urgent intervention by specialists (neurologist, genetics). Also, some hereditary (chromosomal and monogenic) diseases are often combined with the development of motor disorders. The best results are achieved if the early diagnosis of diseases accompanied by movement disorders is carried out using an interdisciplinary approach.

Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon

L-dopa is the most effective drug used to date for management of Parkinson's disease symptoms. Unfortunately, long-term administration of L-dopa often results in development of motor disorders, including dyskinesias. Despite extensive research on L-dopa-induced dyskinesia, its pathogenesis remains poorly understood. We demonstrated previously that L-dopa can be post-translationally incorporated into the C-terminus of α-tubulin in living cells. In the present study, we investigated the effect of the presence of L-dopa-tubulin-enriched microtubules on mitochondrial traffic mediated by molecular motor KIF5B. Using biochemical approaches in combination with experiments on neuronal cell lines and mouse hippocampal primary cultures, we demonstrated that L-dopa incorporation into tubulin is irreversible. Transport of mitochondria along the axon was altered after L-dopa treatment of cells. In L-dopa-treated cells, mitochondria had reduced ability to reach the distal segment of the axon, spent more time in pause, and showed reduced velocity of anterograde movement. KIF5B motor, a member of the kinesin family involved in mitochondrial transport in neurons, showed reduced affinity for Dopa-tubulin-containing microtubules. Our findings, taken together, suggest that tyrosination state of tubulin (and microtubules) is altered by L-dopa incorporation into tubulin; the gradual increase in amount of altered microtubules affects microtubule functioning, impairs mitochondrial traffic and distribution, and this could be relevant in Parkinson's disease patients chronically treated with L-dopa.

PROTECTIVE EFFECT OF SOME SALTS 2-AMINOETHANESULFONIC ACID IN AN EXPERIMENTAL MODEL OF DEGENERATIVE SPINAL CORD INJURY

In this work, we studied the pharmacological activity of zinc and magnesium salts of 2-aminoethanesulfonic acid in white non-linear male rats with amyotrophic lateral sclerosis, which was modeled by neurotoxicantsimplication into the pelvic part of spinal cord. After the reproduction of the pathology in animals, the indices of motor activity were recorded in the Rotarod test, and morphological studies of spinal cord sections stained according to Nisl in the Belshovsky modification were carried out. It was shown that the magnesium salt of 2-aminoethanesulfonic acid (compound LHT-317) to a greater extent reduces the development of motor disorders in experimental animals compared with the control group on the 4th day of observation. The course of intravenous administration of the studied compounds of 2-aminoethanesulfonic acid did not inhibit morphological changes in the spinal cord that develop in degenerative-dystrophic pathology of the central nervous system: connections. Moreover, if, against the background of treatment with zinc salt, the total area of motor zones in animals of the experimental group exceeded that of control rats, then the number of motoneurons did not differ from the control.

Methods for early diagnosis of Parkinson’s disease

Currently, the diagnosis of Parkinsons disease is carried out mainly on the ground of clinical picture. However, long before the development of motor disorders, a number of signs characteristic of parkinsonism can be detected. The review of the literature presents methods to detect non-motor disorders that can be considered as predictors of the disease and it also discusses the issue of the laboratory studies of specific biomarkers for early diagnosis. We suggested to use the combination of olfactory test and questionnaire about vegetative disorders as the most relevant solution for clinical practice. It is recommended to interpret the test data as a sign of extremely high probability of the development of clinical manifestations of Parkinsons disease, and, therefore, as a reason to start preventive therapy.

Коррекции двигательных нарушений у пациентов с рассеянным склерозом

The main cause of occupational and social activity disorders in patients with multiple sclerosis (MS) is motor deficit. The genesis of movement disorders reflects multifocal lesions of various parts of the spinal cord and brain. The patient groups were formed according to the EDSS scale: with mild (EDSS 2,5–4,0 b), moderate (EDSS 4,5–5,5 b) and severe motor disorders (6,0–6,5 b). There was performed neurological examination of patients with an assessment of the cognitive and vestibular functions of the body. The dominant syndromes in the development of motor disorders are central paresis, focal, pelvic and cognitive impairments. The developed complex of rehabilitation measures with the use of a stabilometric complex, a treadmill and physiotherapeutic treatment, made it possible to improve the motor function in patients with multiple sclerosis at all stages of the disease. These measures were implemented in the Republican Clinical and Diagnostic Center for demyelinating diseases in Kazan.

Caudatonigral projections under normal conditions and after an MPTP-induced lesion of the cat nigrostriatal system: Quantitative ultrastructural analysis

Ultrastructural and morphometric studies of caudatonigral synapses located on the nigrothalamic neurons were carried out on intact and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated adult cats. Three types of synapses with different ultrastructural features were found. Morphometric analysis showed that 11.3% of analyzed junctions were caudatonigral synapses; 5.9% and 5.4% of them were located on the somata of nigrothalamic neurons and on their dendrites respectively. Among axo-somatic synapses, the caudatonigral ones amounted to 11.9%: 7.6% were type-I synapses and 4.3% belonged to type-III synapses. Both types had symmetrical contacts and could be considered inhibitory. Caudatonigral axodendritic synapses amounted to 10.6%: 3.2% were of type I; 4.2%, of type III; and 3.2%, of type II synapses with asymmetric contacts. The labelled type-II synapses were found exclusively on the nigrothalamic dendrites. The ultrastructural changes and the statistically significant decrease in the size of caudate axon terminals following the MPTP treatment took place only in the type I exosomatic synapses. It is suggested that the development of motor disorders in the cat after experimentally induced striatal dopamine insufficiency is due to the decrease in the efficacy of caudatonigral influences, which causes disinhibition of GABA-ergic inhibitory nigrothalamic neurons, and to enhanced influences of the latter on the cells of the motor thalamic nuclei.