Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. However, current treatments e.g. dopamine precursors, monoamine oxide inhibitors and COMT inhibitors, do not aim to address the underlying loss of dopamine containing neurons, but rather, most focus on modulating the extant dopamine metabolism.
In studying PD, familial PD cases have been useful in adding to the understanding of pathophysiology. Importantly, they revealed the association of mutations in mitochondrial proteins with PD, thereby implicating mitochondrial dysfunction in the causes of the disease. One of the identified mitochondrial proteins, PTEN-induced putative kinase 1 (PINK1) is usually trafficked to the interior of mitochondria, where it is rapidly degraded. However, in dysfunctional mitochondria, the reduction in proton electrochemical gradient is associated with the failure of PINK1 to traffic to the mitochondrial interior. Instead, PINK1 accumulates on the surface of the cytoplasmic face of the outer mitochondrial membrane, where it recruits another familial PD-implicated protein Parkin. It is the recruitment of Parkin to the depolarized mitochondrion that sets in motion mitophagy and clearance of the dysfunctional mitochondrion. As such, the PINK1-Parkin pathway represents an important quality control mechanism, helping cells to remove dysfunctional mitochondria and the deleterious effects they cause due to the release of reactive oxygen species or pro-apoptotic factors.
A key question in this mechanism becomes, what is regulating PINK1? The article by the Fon lab at McGill university helps answer part of this question. By selectively screening mitochondrial proteases using RNA-mediated interference, they were able to identify mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP as being involved in the degradation of PINK1. Of these, MPP appears to be the major factor in PINK1 turnover, with even slight reductions in MPP activity resulting in PINK1 accumulation at the mitochondrial surface. The authors suggest that potentiation of the PINK-1-Parkin pathway, possibly by low level inhibition of MPP, could be an avenue to explore in treating PD by increasing the stringency for mitochondrial function and thereby reducing oxidative stress in dopaminergic neurones. While a single eukaryotic cell has over 1000 mitochondria, one has to assume that altering the fundamental balance of mitochondrial turnover is going to be fraught with perils.
However, as highlighted by the rather sparse KEGG PD pathway map, all advances that elucidate the proteins and events in PD are vital in the search for a unified, global understanding of PD, be it familial or idiopathic, and the hope for a therapy that can address the underlying molecular mechanism.
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