It's called PINK1 and although it has been known for 20 years, this is the first time that scientists have managed to see it clearly in work published in ScienceThis protein, essential for the destruction of mitochondria when they no longer function, is mutated in many patients with early-onset Parkinson's disease. This new work, the culmination of several years of effort, could allow the exploration of new treatment avenues for these patients.
Early Parkinson's Disease Caused by Mutated Proteins
5 to 10% cases of Parkinson's disease, which affects nearly 200,000 people in France alone, are due to a genetic mutation circulating among members of the same family. Of these mutations, the two most common involve the proteins Parkin and PINK1, and are responsible for an early onset of the disease between approximately 21 and 45 years of age. Patients with PINK1 mutations have a median age of onset of symptoms of 32 years, with tremors, bradykinesia (slow movements) and rigidity very similar to other Parkinson's patients, according to the database. GeneReviews.
PINK1 is so important that its alteration can cause the disease because it triggers the destruction of damaged mitochondria (the cells' powerhouses). This process, called mitophagy, prevents these dysfunctional mitochondria from accumulating in the cell, which would lead to its death. This is precisely what happens in patients with a mutated version of PINK1.
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The first image of PINK1 docked to a mitochondria
“ This is the first time we can see how PINK1 docks to the surface of damaged mitochondria", explains researcher Sylvie Callegari, first author of this work. To do this, it must form a dimer (a pair with another PINK1) symmetrically, then penetrate from the outer membrane to the inner membrane of the mitochondria through a succession of precise interactions with different proteins of the mitochondrial membrane.
A path meticulously traced using cryo-electron microscopy observations, which allows 3D images of biological tissues to be obtained. With a precision of 3.1 Angstroms (0.31 millionths of a millimeter), it reveals in particular the structure of the PINK1 dimer anchored to the surface of the mitochondria (see the illustration above).
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In patients, PINK1 proteins are mutated in two places, precisely those that allow them to interact with another protein called TOM7. However, TOM7 guides the entry and exit of PINK2 through the mitochondrial membrane. Without TOM7, PINK1 is no longer stabilized and is continuously degraded. This structure provides multiple unexplored avenues to stabilize PINK1 in mitochondria, in order to develop much-needed therapeutic options for patients with Parkinson's disease.", the researchers conclude.
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