The protein alpha-synuclein (aSN) has long been known as a main cause in Parkinson's disease and Lewy Body Dementia, for example, when it forms lumpy protein aggregates that destroy cell function - but aSN in its natural form, without clumping, has not had a concrete, known function.
An international research team has now demonstrated that natural aSN is an important activator of an essential calcium pump in the cell membrane.
Previously, the protein calmodulin was the only known activation factor of PMCA, but the researchers now add another important player and show that the activation of PMCA by aSN takes place in negatively charged membrane environments, complementary to calmodulin, which acts in neutral and possibly positively charged lipid environments.
The senior author explains: "The activation appears to be of particular importance in the presynaptic area of neurons, which is responsible for transmitting signals in the brain's neural network. It is known that aSN accumulates in the presynaptic compartment, and our study shows, for the first time, that aSN and PMCA appear together in this area. In addition, we show that aSN stimulates calcium excretion from neurons, and not least that aSN significantly increases the activity of the PMCA."
In addition, the researchers show by mathematical network modeling that PMCA activation likely to be of key importance for the calcium balance (homeostasis), when neurons signal repeatedly, and calcium therefore enters the cell constantly. aSN's activation of PMCA thus prevents a build up of calcium that would be toxic to the cell.
Another author states: ”Our laboratory has previously shown that early clump stages of aSN activate another calcium pump, SERCA, which sits in an internal organelle of the cell (endoplasmic reticulum), but SERCA is not activated much by soluble aSN. Oppositely, PMCA is activated a lot by soluble aSN and almost not by clumped aSN .”
Calcium regulation by PMCA and SERCA is essential for all cells, not least neurons, so if a pathological condition is associated with transitioning from natural aSN to clumped aSN, there is also a shift in aSN activation from PMCA to SERCA, and calcium regulation is thus strongly affected. It changes a multitude of processes, and ultimately leads to cell death.
Calcium regulation is fundamental to the function of all cells, including neurons. It plays a crucial role in signal transmission, particularly in the presynaptic area where native aSN is typically found. When aSN clumps, this balance is therefore shifted from PMCA- to SERCA-activated calcium regulation, and this changes the calcium balance in cells. This is thought to take place early in diseases such as Parkinson's.
This newfound understanding of aSN's dual role in calcium regulation could have profound implications for unravelling the early disease processes, especially in Parkinson's disease. By identifying the shift from natural aSN activation of PMCA to clumped aSN activation of SERCA, researchers can gain insights into the mechanisms that underlie the onset and progression of neurodegenerative conditions.
As researchers continue to explore the intricate relationship between aSN and calcium pumps, it opens the door to potential diagnostic and therapeutic strategies aimed at exploring and mitigating the early disruptions in calcium regulation.
The discovery of natural aSN's role in calcium pump activation represents an important step towards understanding the complex biology of neurodegenerative diseases and how we might be able to cure them.
https://www.embopress.org/doi/full/10.15252/embj.2022111122
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fmonomeric-945&filter=22
Monomeric α-synuclein activates the plasma membrane calcium pump
- 956 views
- Added
Latest News
Which of the two DNA strand…
By newseditor
Posted 16 Jun
Microglia depletion prevent…
By newseditor
Posted 16 Jun
Colorectal cancer stem cell…
By newseditor
Posted 16 Jun
Paranoia in the brain
By newseditor
Posted 16 Jun
In-vitro 3D culture of func…
By newseditor
Posted 15 Jun
Other Top Stories
Does 'harsh parenting' lead to smaller brains?
Read more
Filters from tree branches to purify drinking water
Read more
How teeth sense the cold
Read more
Why the brain enjoys music
Read more
How brain encodes odor
Read more
Protocols
Bioengineered human colon o…
By newseditor
Posted 14 Jun
Development of an efficient…
By newseditor
Posted 12 Jun
A co-culture system of macr…
By newseditor
Posted 10 Jun
Analysis of 3D pathology sa…
By newseditor
Posted 08 Jun
Long-term expandable mouse…
By newseditor
Posted 07 Jun
Publications
Pathways for macrophage upt…
By newseditor
Posted 16 Jun
Common and distinct neural…
By newseditor
Posted 16 Jun
Strand-resolved mutagenicit…
By newseditor
Posted 16 Jun
Innate-like T cells in live…
By newseditor
Posted 16 Jun
Membrane to cortex attachme…
By newseditor
Posted 16 Jun
Presentations
Myelin plasticity in the ve…
By newseditor
Posted 10 Jun
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar