Key to New Dementia Treatments With Molecular 'Scaffold'

Professor Chris Miller, from the Institute of Psychiatry at King's and lead author of the paper, says: "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."

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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. TPD-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 TPD-43 affected mouse cells in a dish. They found that higher levels of TPD-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 concludes: "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."

Source: Eurekalert