Researchers at King's College London have discovered how a
molecular 'scaffold' which allows key parts of cells to interact,
comes apart in dementia and motor neuron disease, revealing a
potential new target for drug discovery.
Researchers looked at two components of cells: mitochondria, the
cell 'power houses' which produce energy for the cell; and the
endoplasmic reticulum (ER), which makes proteins and stores calcium
for signalling processes in the cell. ER and mitochondria form
close associations and these interactions enable a number of
important cell functions. However the mechanism by which ER and
mitochondria become linked has not, until now, been fully
understood.
Professor Chris Miller, from the Department of Neuroscience at
the Institute of Psychiatry at King's said: "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. 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."
By studying cells in a dish, the researchers discovered that an
ER protein called VAPB binds to a mitochondrial protein called
PTPIP51, to form a 'scaffold' enabling ER and mitochondria to form
close associations. In fact, by increasing the levels of VAPB and
PTPIP51, mitochondria and ER re-organised themselves to form
tighter bonds.
Many of the cell's functions that are controlled by
ER-mitochondria associations are disrupted in neurodegenerative
diseases, so the researchers studied how the strength of this
'scaffold' was affected in these diseases. TDP-43 is a protein
which is strongly linked to Amyotrophic Lateral Sclerosis (ALS, a
form of motor neuron disease) and Fronto-Temporal Dementia (FTD,
the second most common form of dementia), but exactly how the
protein causes neurodegeneration is not properly understood.
The researchers studied how TDP-43 affected mouse cells in a
dish. They found that higher levels of TDP-43 resulted in a
loosening of the scaffold which reduced ER-mitochondria
bonds,affecting some important cellular functions that are linked
to ALS and FTD.
Professor Miller concluded: "Our findings are important in terms
of advancing our understanding of basic biology, but may also
provide a potential new target for developing new treatments for
these devastating disorders."
The paper, ER-mitochondria associations are regulated by the VAPB-PTPIP51
interaction and are disrupted by ALS/FTP-associated TDP-43, is
published in Nature Communications.