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Parkinson’s May Be Caused By A Failure To Remove Faulty Mitochondria

Posted on 9 September 2016

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Research at Stanford have located a defect that may be common to both sporadic and familial Parkinson’s disease

Parkinson’s disease is characterised by a progressive destruction of dopaminergic cells in the substantia nigra, and affects more than 10 million people worldwide; making it the 2nd most common neurodegenerative disorder in the developed world. A number of features of Parkinson’s have been identified, including mitochondrial dysfunction and a failure of the garbage disposal system in these cells – allowing an aggregate called alpha synuclein to build up. It’s not clear what actually initiates the disease however, and whether these hallmarks are causes in themselves, or merely a reaction to another process. 

“We’ve found a molecular biomarker that characterizes not just familial cases of Parkinson’s, in which a predisposition for the disease is clearly inherited, but also the condition’s far more prevalent sporadic forms, for which the genetic contribution is either nonexistent or not yet discovered” 

α-Synuclein staining of a Lewy body from a patient with Parkinson's disease

α-Synuclein staining of a Lewy body from a patient with Parkinson’s disease

Understanding familial Parkinson’s disease

The most common familial mutations in Parkinson’s are centred around a gene called LRRK2, but until now researchers were unsure how these mutations led to the disease. Now, scientists at Stanford have determined that defective LRRK2 inhibits the ability to remove damaged and toxic mitochondria, which then continues to spill out harmful molecules and clogs up the cell. 

Removing faulty mitochondria

Mitochondria are the cell’s engines and are particularly important in dopaminergic neurons, which supply dopamine for a huge range of processes in the brain. They have a high work load and require a healthy population of mitochondria to sustain this. Because mitochondria are constantly churning out energetic molecules and free radicals, they’re especially vulnerable to damage and mutations. Healthy cells are quite capable of noticing this and disposing of any undesirables, but an LRRK2 defect essentially inhibits this removal. 

Credit: Birsa, Nicol, et al.

Credit: Birsa, Nicol, et al. “Mitochondrial trafficking in neurons and the role of the Miro family of GTPase proteins.” Biochemical Society Transactions 41.6 (2013): 1525-1531.

For the cell to remove mitochondria they must be severed from the cytoskeleton they’re bound to, and this is achieved through removing a protein called Miro. Normal LRRK2 forms a complex with Miro to facilitate cytoskeleton detachment, but defective LRRK2 either delays or prevents this removal altogether. 

Linking sporadic to familial

When a Stanford team analysed 20 lines of different fibroblasts cultured from individuals with familial Parkinson’s mutations, sporadic Parkinson’s, and a healthy control group, they found that all Parkinsonian cells showed delayed and diminished mitochondrial removal (after the scientists had induced mitochondrial damage). In an effort to explore this curious discovery further, they created dopaminergic nerve cells from these fibroblasts and again determined that the removal process was substantially delayed in these cells. Furthermore, when these cells were put under increased free radical stress they died faster and in greater numbers in comparison to those from the control group.

“The healthy cells could handle higher free-radical concentrations. But the Parkinson’s cells were more prone to dying under those conditions, which are apt to occur in the energy-intensive, midbrain, dopamine-producing nerve cells that degenerate in Parkinson’s disease” 

Possible drug targets

The same team was able to partially correct this delay by reducing the levels of Miro protein in these cells. Far fewer of the cells died and responses mirrored healthy subjects’ cells. Indeed, in a fruit fly model of Parkinson’s lowering levels of Miro proved able to restore movement deficits. While individuals with sporadic versions of the disease may not have genetic defects in LRRK2, it may be that other cellular processes or stress are inhibiting the binding and removal of Miro; making the protein a potential new drug target. Current treatment of Parkinson’s is sadly inadequate and in serious need of new therapies. 

“Existing drugs for Parkinson’s largely work by supplying precursors that faltering dopaminergic nerve cells can easily convert to dopamine. But that doesn’t prevent those cells from dying, and once they’ve died you can’t bring them back. Measuring Miro levels in skin fibroblasts from people at risk of Parkinson’s might someday prove beneficial in getting an accurate, early diagnosis. And medicines that lower Miro levels could prove beneficial in treating the disease”

Read more at EurekAlert

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