The earliest description of “shaking palsy” were already given in 1817 by James Parkinson, yet nearly 200 years later the exact causes of the development of Parkinson’s disease are still unexplained. There is broad recognition that a multifactorial event is concealed behind akinesia, tremors and so forth. Of course, genetic causes have been targeted and heavily researched – with the result that a number of genes are suspected of being involved in the pathogenesis of Parkinson’s. At the same time science gathers the evidence that autoimmune changes, just like mitochondrial dysfunctions, share responsibility for dopamine deficiency.
Now a research group led by Dr. Michel Desjardins from the University of Montreal and Dr. Heidi McBride from McGill University has made a very exciting discovery, which might establish a connection between the three pathogenetic components – genetically, autoimmunologically and in mitochondrial terms: In a recent study they were able to observe that a dysfunction of genes PINK1 and Parkin in vitro and in vivo can cause mitochondrial antigen presentation by MHC-1 molecules: through this, cytotoxic T cells may be paving the way for the destruction of cells.
It was found that antigen presentation is ultimately activated by the pathway involved in transporting mitochondrial vesicles to the endosomes. Normally, PINK1 and Parkin proteins would inhibit these transport paths. However if the genes were missing, this inhibition was absent. This mechanism could offer an approach to elucidate the breakdown of dopaminergic neurons occurring with Parkinson syndromes.
The results, however, are not only important for Parkinson’s patients. This is because the mechanism showing how mitochondrial antigen presentation is controlled via the transport of vesicles was demonstrated by the researchers for the first time. “The role PINK1 and Parkin play in inhibiting mitochondrial antigen presentation might not be decisive in relation to Parkinson’s disease alone, but may also causally underlie other autoimmune diseases such as diabetes, lupus and primary biliary cirrhosis, with which a connection to the mitochondrial antigen presentation has already been able to be deduced”, comments Dr. Desjardins on the study results.
Freezing? In research – not happening at all
Things are not exactly moving anywhere fast in relation to bradykines in neuroimmunological research: it was first postulated in 2014 by Cebrian et al. that neurons express MHC-1 molecules to a relevant extent, thus setting the stage for T-cell activation within the neural network. Previously, it had been assumed for decades that neurons are protected from immune system attacks: “This idea made sense, because our brain cannot – apart from rare instances – replace cells destroyed by the immune system. Yet unexpectedly we found that some neuron types can present antigens”, Dr. Sulzer, a member of the working group, offered as his comment on the situation at the time.
The neuron types mentioned were interestingly catecholaminergic neurons of the substantia nigra and locus coeruleus. The declaration was thereby virtually made that the dopamine-producing substantia nigra, a central location of the pathological process involved in the medical condition Parkinson, is a tissue vulnerable to T-cell mediated destruction.
The researchers in their study model MHC-1 induced expression via the cytokine interferon-gamma (IFN-γ). IFN-γ is produced by the microglia, the macrophages of the brain, in the CNS. Microglia in turn may themselves be activated – by α-synuclein (among other substances), the main component of the Lewy-body, therefore by another cytological correlate of Parkinson’s disease.
Taking small steps towards new therapies
The new findings open up new approaches for the therapy of Parkinson’s disease and provide the prospective ability of being able to draw on targeted immunological therapies in the future.
Vesicular transport in being a regulator of mitochondrial antigen presentation could represent a target for such targeted therapy and the basis for the development of new drugs. Thus far the treatment of Parkinson’s disease has mainly taken a symptomatic approach. Via substitution of dopamine, of L-DOPA in particular, the symptoms can often be more or less controlled, especially during the first years of the disease. Neurodegeneration however progresses and causal therapeutic approaches have been non-existent until now.
The option to modulate very general autoimmune processes in Parkinson disease has also come into focus. One possibility could be to halt the inflammatory reaction at the proinflammatory cytokine level. In addition to increased levels of IFN-γ, Parkinson’s patients also demonstrate elevated levels of IL-1, IL-6 and TNF-α. The use of monoclonal antibodies as TNF-α inhibitors could represent a promising option.
What’s more glucocorticoids are supposed to come into the picture with their anti-inflammatory effects and have been widely used in studies of inflammatory processes within the brain. With dexamethasone in particular a protective effect on dopaminergic neurons was able to be observed.
Risk through long-term use of anti-inflammatory drugs drops
The same applies to nonsteroidal drugs (NSAIDs) such as aspirin or ibuprofen: There is evidence that long-term use reduces Parkinson risk by more than 20%, which may offer favourable evidence of high therapeutic potential in this substance class. Both the tetracycline-analogue minocycline and the opioid antagonist naloxone also show anti-inflammatory effectiveness beyond the blood-brain barrier.
The new findings of course need to be further researched and new therapies cannot simply be pulled out of the hat. Nevertheless, the results raise the future hope of freeing those afflicted from their physiological freezing – and bringing this second most frequent of neurodegenerative diseases to a halt.