Molecular scaffold key to neurodegenerative disease

A molecular scaffold that allows key parts of the cell to communicate falls apart in dementia and motor neuron disease; a finding which offers a new target for drug discovery. Researchers from King’s College London looked at two components of the cell, the mitochondria and the endoplasmic reticulum (ER), which makes proteins and stores calcium in the cells for signalling processes. The two form close associations which enable a number of important cell functions, but how they became linked was previously unclear. By studying cells in a dish, researchers found an ER protein called VAPB which binds to a mitochondrial protein called PTPIP51 to form a molecular scaffold which allows the close linkage. By increasing the levels of both proteins, the mitochondria and ER reorganised themselves to form even tighter bonds. “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,” said Professor Chris Miller from the Department of Neuroscience. “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 and motor neuron disease.” Many of the cell’s functions are controlled by the ER-mitochondrial associations and become disrupted in neurodegenerative diseases, so the team studied how the strength of the scaffold might be affected in these diseases. They focussed on TPD-43, a protein strongly linked to Amyotrophic Lateral Sclerosis (ALS), a form of motor neuron disease, and Fronto-Temporal Dementia, the second most common form of dementia. How the protein causes neurodegeneration is not properly understood, so the researchers studied how it affected mouse cells in a dish. They discovered that higher levels of TPD-43 caused a loosening of the scaffold, reducing the bonds and affecting important cellular functions. “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,” said Miller. ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are distributed by ALS/FTP-associated TDP-43