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Gene linked to Parkinson’s disease regulates communication between neurons

PTEN-induced putative kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene which has been altered in patients with Parkinson’s disease. It works as a “guard” because it can detect if there are damages in the organelle responsible for producing energy in cells (mitochondria) and trigger selective destruction mechanisms, thus avoiding damage propagation.

Neurons with PINK1 gene mutation do not recognize there is an issue in the mitochondria, and therefore have an energy deficiency they cannot solve, hence comprising their survival.

UNal Psychologist and Neurosciences Ph.D. César Javier Hernández says that they have analyzed the function of this gene and its neuronal level connection. He says the PINK1 encoded protein-kinase has an important function within the mitochondria as it regulates the dynamic processes of neurons and contributes to the production of energy and inhibiting cell death.

“What the PINK1 encoded protein-kinase does is protect neurons from dying, however a mutation in the protein-kinase leads to neuronal death which is the main cause of the clinical profile of Parkinson’s disease,” said Hernández.

Besides its function within the mitochondria, the interest of the expert on the PINK1 gene encoded protein is the role it has in neuronal communication which occurs mainly on the dendritic spines and particularly on synapsis.

“Our research revealed that diminishing the PINK1 gene expression level, there are changes on the dendritic spines in form, density, and quantity,” claims Hernández.

UNal Institute of Genetics’ Neuronal Death Research Group Director Professor Gonzalo Arboleda, adds that using the PINK1 expression silencing model developed by the group the amount of hippocampus neuron immature dendritic spines increased, suggesting that the neuron could be over-excited leading to neuronal death due to over-triggering, or alternatively a blockage in dendritic spine maturation.

“What we observed is that when the PINK1 gene is absent, there is a lack of protein expression in locations where neurons multiply, both at the pre and post-synapsis level, suggesting that there are communication alterations with this function, ” said Arboleda.

Although the hippocampus is not the main structure impacted by the disease, the gene expression hippocampus silencing model was looking to analyze the synapsis between these types of neurons and the hippocampus has intimate associations such as memory, most affected during Alzheimer’s and progression of Parkinson’s disease, which ultimately leads to dementia.

“This shows there is an interrelationship between the processes that occur in different diseases such as Alzheimer’s and Parkinson’s and PINK1 gene-encoded proteins, which play an important part in both diseases,” said Arboleda.

Neuronal culture

In order to silence the expression of the PINK1 gene, they had a mouse hippocampus neuron culture and incorporated genetic material into the neurons by using a procedure known as transfection  (the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells.)

“This genetic material was introduced into neurons using a plasmid, thus allowing handling of protein expression by interfering mRNA transcription of the PINK1 gene encoding,” said the researcher.

Hernández says that they also used another plasmid which encoded a green fluorescent protein which allows seeing the dendritic tree of the neuron, and supported by photographic morphological analysis and viewing dendritic spines with confocal fluorescent microscopy.

Parkinson’s and Alzheimer’s challenges

Parkinson’s disease is classified as the second most common neurodegenerative disease after Alzheimer’s. According to the researcher, there are approximately 220,000 cases of Parkinson’s disease which show symptoms of tremor, stiffness, and bradykinesia and later in the disease some patients even suffer from cognitive and psychiatric issues such as dementia.

Currently, the elderly world population has a tendency to grow; therefore it is estimated that the amount of Parkinson’s will also increase, turning into a serious public health issue.

For research director Arboleda, these type of analysis models has helped identify new functions linked to the PINK1 encoded protein,  important in several essential processes for the correct function of neurons, as the absence of the protein kills the neuron, as it acts like a neuronprotector by recognizing a damaged mitochondria and engulfs the cell so it does not enter the process of cell death, and additionally it is also essential for correct operation of the synapsis.

The expert also said the close to 95% of Parkinson’s cases are sporadic, in other words, there is no family connection and a minority are from gene mutations such as the PINK1 which produces the inherited disease. Researching the basic function of these rare genes opens the possibility of understanding the most frequent and complex forms.

Both UNal experts agree that these types of developments contribute to the challenge of searching alternative pharmacological remedies such as manipulating the expression of the PINK1 gene to produce greater endogenous function and also strengthen the mitochondrial function as well as the general synapsis process for better neuroprotection.

 

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