Sarah Khatkhatay, SK Somaiya, Vidhyadhar
Tau proteins are proteins that exhibit the function of stabilizing microtubules. These are present abundantly in the nerve cells. They have isolated as a microtubule-associated protein and promote the assembly and stability of the microtubules. Microtubules play a fundamental role in the division of the cell and neuronal activity. A disruption of the microtubule network might be due to the loss of tau protein function. Hyper phosphorylation of the protein depresses the biological activity of tau. Destabilization of microtubules after dissociation of tau protein contributes to toxicity in neurodegenerative diseases. Around 80 diseases are caused by missense and intronic mutations in the tau genes have been found.
When tau proteins become defective and are unable to stabilize microtubules, pathologies of the nervous system develop. As in Alzheimer’s disease, there are intraneuronal neurofibrils composed of the microtubule-associated protein tau, this reduction in the endogenous levels of tau proteins has been suggested as a possible therapy. This is unlike Parkinson’s disease dementia and Lewy body dementia. Together the two diseases are the second most common cause of neurodegenerative dementia after Alzheimer’s disease. Here, the diseases are characterized by abnormal deposits of misfolded alpha-synuclein protein in brain neurons. Alpha-synuclein is a protein abundant in dopamine-producing nerve cells or neurons. However, in Parkinson’s disease, it misfolds and clumps together to form aggregates which are called Lewy Bodies.
Volpicelli- Daley, associate professor of neurology used a Parkinson’s disease model she developed 11 years ago and applied very low concentrations of altered alpha-synuclein, which has already taken on a pathological confirmation to either in vitro or in vivo neurons. The nerve cells pick up some fibrils. Inside the cell, the altered alpha-synuclein attracts the naturally present soluble alpha-synuclein in the neurons. This leads to the transformation of the soluble alpha-synuclein into pathological and insoluble aggregates that impair neuron function, leading to apoptosis. The modified alpha-synuclein are morphologically similar to those found in the Parkinson’s disease brains after death.
Template alpha-synuclein inclusion formation model
This disease model was used to compare the neurons that produce the normal amount of tau proteins against the mutant neurons that lack either one or both of the genes for tau, thus having less or no tau protein. The UAB researchers found no difference in the wild-type control. The endogenous tau protein did not contribute to disease progression as the heterozygous or knockout tau mutants did not show protection as expected. The researchers showed that there was an interaction between tau and alpha-synuclein in the cells, as both proteins are localized in presynaptic terminals of the primary culture neurons and cortex of the mouse brain. Several in vitro studies showed that the two proteins interact with each other. However, in vitro, having fewer or no tau proteins did not prevent fibril-induced alpha-synuclein inclusion formation in primary hippocampal neurons. Similarly in mice, the reduction or complete absence of tau did not prevent fibril-induced alpha-synuclein inclusion formation in the motor control or limbic areas of the brain, when measured six weeks to six months after fibril injections. As the alpha-synuclein fibrils in the mouse model caused the death of half of the wild-type neurons which produce the neurotransmitter dopamine. On the other hand, the dopaminergic neurons in tau heterozygous mice show the same amount of neuron death, indicating no protection. The loss of dopaminergic neurons is associated with Parkinson’s disease. In conclusion, the reducing tau proteins did not have any major impact on the phenotypes of mice with fibril-induced alpha-synuclein inclusions. Thus, the reduction of endogenous tau did not influence the formation of template alpha-synuclein inclusion or the loss of dopamine neurons.
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References:
- Lindsay E. Stoyka, Casey L. Mahoney, Drake R. Thrasher, Drèson L. Russell, Anna K. Cook, Anner T. Harris, Ashwin Narayanan, Tiara P. Janado, David G. Standaert, Erik D. Roberson, Laura A. Volpicelli-Daley. Templated α-Synuclein Inclusion Formation Is Independent of Endogenous Tau. eneuro, 2021; 8 (3): ENEURO.0458-20.2021 DOI: 10.1523/ENEURO.0458-20.2021
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