Scientists have identified previously undiscovered changes that occur at a cellular level in dementia and motor neuron disease. Professor Chris Miller of King’s College London, UK, and his team examined a molecular “scaffold” that allows crucial parts of bodily cells to interact.
They examined the cell components involved in this structure, called mitochondria and endoplasmic reticulum (ER). Mitochondria produce energy for the cell, and ER makes proteins and stores calcium for cell signaling. Together they form tight structural links that facilitate many cell functions.
Mitochondria receive calcium, an important signaling molecule inside nerve cells, from ER so they can make energy. But too much calcium is damaging, so the flow of calcium has to be very carefully controlled.
Mitochondria and ER are often physically connected by proteins, and when calcium signalling between mitochondria and ER goes wrong it can trigger fronto-temporal dementia, the second most common form of dementia, and neurodegenerative diseases such as amyotrophic lateral sclerosis (a form of motor neuron disease). But the exact methods by which mitochondria and ER become linked have been unclear until now.
Laboratory tests showed that an ER protein called VAPB binds to a mitochondrial protein called PTPIP51 making the linking ‘scaffold.’ When levels of the proteins VAPB and PTPIP51 are increased, mitochondria and ER form even tighter bonds, say the team.
In tests on mouse cells, the team found that higher levels of a protein called TPD-43 led to a loosening of the scaffold between ER and mitochondria. This chimes with earlier findings that a build up of TDP-43 is commonly seen in fronto-temporal dementia and amyotrophic lateral sclerosis.
It can also begin the disease process in rodent tests. What’s more, the importance of TDP-43 in these diseases is underscored by research showing that mutations in the TDP-43 gene are responsible for the conditions in some patients.
“At the molecular level, many processes go wrong in dementia and motor neuron disease, and one of the puzzles we’re faced with is whether there is a common pathway connecting these different processes,” says Professor Miller.
“Our study suggests that the loosening of this ‘scaffold’ between the mitochondria and ER in the cell may be a key process in neurodegenerative diseases such as dementia or motor neuron disease.”
Specifically, it appears excess TDP-43 causes damage to the ER-mitochondria scaffold via disruption to calcium signalling pathways.
The team hopes that their new discoveries on TDP-43 and the VAPB/PTPIP51 interaction that regulates ER-mitochondria links may help “provide a potential new target for developing new treatments for these devastating disorders.” Their report is published in the journal Nature Communications.
A separate in-depth study of Alzheimer’s disease and the ER-mitochondria link was carried out by a team from Columbia University Medical Center, New York, N.Y. They carried out lab tests that showed that “altered ER-mitochondrial communication lies at the heart of Alzheimer’s disease pathogenesis.”
They add that many of the changes seen in patients with Alzheimer’s disease, such as raised cholesterol and glucose levels, and changes to cell membranes “are the very functions that are associated with connections between ER and mitochondria.”
These changes are routinely seen in Alzheimer’s disease patients. Hence, ER-mitochondrial communication “could play a hitherto unrecognized and critical role in the pathogenesis of Alzheimer’s disease that may help us to understand better this devastating disease and might harbor potential targets for new treatment strategies.”
Further research has been carried out on familial Alzheimer’s disease. This is a rare form of the condition that tends to be more severe and have an early onset (below 65 years). Among these patients too, there seems to be impaired ER/mitochondria interaction. This appears to be the cause of problems with motor coordination in the cerebellum region of the brain.
Other studies have discovered that calcium signalling between mitochondria and ER also goes wrong in Parkinson’s disease, the degenerative nervous system disease. A ‘rogue’ protein called alpha-synuclein may be to blame.
It was seen in mitochondria/ER links in cell samples and brain tissue from humans and mice, and found to form sticky clumps, known as Lewy bodies, which clog up the affected nerve cells.
“We believe that our results have far-reaching implications for both our understanding of alpha-synuclein and the treatment of neurodegenerative diseases characterized by the abnormal accumulation of alpha-synuclein,” they write.
“This will open up a whole new avenue for developing drugs that preserve these essential connections.”
Stoica, R. et al. ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTP-associated TDP-43. Nature Communications, 3 June 2014 doi:10.1038/ncomms4996
Area-Gomez, E. et al. Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. The EMBO Journal, 5 November 2012, doi: 10.1038/emboj.2012.202.
Guardia-Laguarta, C. et al. α-Synuclein is localized to mitochondria-associated ER membranes. The Journal of Neuroscience. 1 January 2014 doi: 10.1523/JNEUROSCI.2507-13.2014.
Sepulveda-Falla, D. et al. Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis. The Journal of Clinical Investigation, Volume 124, Issue 4, 1 April 2014, doi:10.1172/JCI66407