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Parkin Function in Parkinson Disease.

In 1886, architect Louis Sullivan wrote "Whether it be the sweeping eagle in his flight, or the open apple-blossom, the toiling work-horse, the blithe swan, the branching oak, the winding stream at its base, the drifting clouds, over all the coursing sun, form ever follows function and this is the law. Where function does not change, form does not change." (1)

Nature at molecular, cellular, and systems levels is perhaps one of the most efficient examples of "form ever follows function." However, when natural form is beset by aberrantly coded DNA, as in the case of pathologic gene mutations, the principle is turned on its head to "dysfunction ever follows form."

As reviewed by Arkinson and Walden recently in Science, researchers are nearing a solution to the 20-year question of how mutations in the Parkin gene drive the 5%-10% of familial, autosomal recessive forms of Parkinson disease (ARPD) (2). ARPD mostly derives from mutations in the Parkin gene, which encodes an E3 ubiquitin ligase involved in mitochondria homeostasis. PTEN-induced putative kinase 1 (PINK1) kinase regulates Parkin function, and loss-of-function mutations in PINK1 are also associated with ARPD. Although it is known that PINK1 phosphorylation activates Parkin, it is still unclear how phosphorylation or cooperative binding mitigates Parkin autoinhibition and elicits conformational changes for subsequent ubiquitination events to occur. Generalized knowledge of a sequence variant encoding these gene products is therefore very limited. Only with a complete structural understanding will therapeutic strategies become apparent and insights into the severity of specific Parkin mutations realized, thus allowing clinical laboratory results to not only help patients know whether they have a Parkin mutation but also enable them to be therapeutically treated and their care better managed.

Herein lies the significance of structural information to clinical laboratories and ultimately patients: deciphered molecular structures allow for our data to be potentially richer and more actionable. Examples are numerous of the medicinal and diagnostic insights and benefits of elucidated structures. For instance, structure-activity studies led to tyrosine kinase inhibitor imatinib for treating BCR/ABL positive chronic myeloid leukemia. Furthermore, disease manifestation in sickle cell anemia is directly correlated to protein structure linked to genetic mutations, and dementia disease progression directly correlates to aggregate protein structures.

Clinical benefit is not limited to structural information of large molecules. One might consider the utility of identifying small molecule chirality when interpreting the source of methamphetamine exposure; structure homology of opioid receptor agonists versus the slight structural nuances of naloxone permitting its life-saving receptor antagonist function; and the critical nature of enantiomeric purity of therapeutics, the case of thalidomide being of historic significance.

Therefore, although sequence variant information or a concentration of a protein isoform is the resulted information from laboratory to clinician, it is the enormous library of information behind those numbers, including structural data, that demarcates the significance of those results.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

Received August 6, 2018; accepted August 9, 2018.

DOI: 10.1373/clinchem.2018.294637

References

(1.) Sullivan LH. The Tall Office Building Artistically Considered. Lippincott's Magazine 1896;57:403-9.

(2.) Arkinson C, Walden H. Parkin Function in Parkinson's Disease. Science 2018;360: 267-8.

Kelly Doyle *

Intermountain Healthcare, Central Laboratory, UT.

* Address correspondence to the author at: Central Laboratory, 5252 South Intermountain Drive, Murray, UT 84157. Fax 801-507-2314; e-mail kelly.doyle@imail.org.
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Title Annotation:News & Views
Author:Doyle, Kelly
Publication:Clinical Chemistry
Date:Nov 1, 2018
Words:649
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