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This study identifies a structural mechanism called "unlatching" that explains how many Parkinson's disease-associated mutations cause LRRK2 protein dysfunction. The researchers found that unlatching mutations alter LRRK2's shape, increasing its localization to cell membranes where it abnormally phosphorylates substrate proteins, and they identified decreased S935 phosphorylation as a measurable biomarker of this conformational change. This framework successfully categorizes a large class of pathogenic LRRK2 variants and explains variants like I2020T that were previously poorly understood.
Why it matters
This research provides a unified explanation for how diverse genetic mutations cause the same disease through a common structural mechanism. The identification of S935 phosphorylation as a conformational biomarker offers a practical diagnostic tool for identifying patients with LRRK2-driven Parkinson's disease and could enable better patient stratification for targeted therapies.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Gain-of-function of leucine-rich repeat kinase 2 (LRRK2) is a common cause of Parkinson’s disease (PD). In its autoinhibited state, the leucine-rich repeats of LRRK2 block the kinase active site, preventing substrate phosphorylation. Displacing the repeats (‘unlatching’) primes LRRK2 for activity. Preferential unlatching causes increased substrate phosphorylation of the PD allele LRRK2[R1441H], but not LRRK2[G2019S]. Here, we define a large class of PD-associated ‘unlatching’ mutations based on their effect on LRRK2 conformation. Unlatching mutants show increased localization to membranes, the site of LRRK2’s Rab substrates. Unlatching mutants are also characterized by decreased LRRK2 S935 phosphorylation, which we define as a biomarker of conformation. This framework resolves the mechanism of variants such as I2020T, which structural studies could not predict. Overall, we establish unlatching as a unifying mechanism for most PD-linked variants and describe measurable readouts for identifying LRRK2-driven disease.
Source: Conformation governs cellular behaviors of LRRK2 Parkinson's disease variants