Responsiveness to distracting stimuli, though increased in Parkinson's disease, is decreased in asymptomatic PINK1 and Parkin mutation carriers

Pathogenic mutations in the Leucine-rich repeat kinase 2 (LRRK2) are the predominant genetic cause of Parkinson's disease (PD). They increase its activity, resulting in augmented Rab10-Thr73 phosphorylation and conversely, LRRK2 inhibition decreases pRab10 levels. Currently, there is no assay to quantify pRab10 levels for drug target engagement or patient stratification. To meet this challenge, we developed an high accuracy and sensitivity targeted mass spectrometry (MS)-based assay for determining Rab10-Thr73 phosphorylation stoichiometry in human samples. It uses synthetic stable isotope-labeled (SIL) analogues for both phosphorylated and nonphosphorylated tryptic peptides surrounding Rab10-Thr73 to directly derive the percentage of Rab10 phosphorylation from attomole amounts of the endogenous phosphopeptide. The SIL and the endogenous phosphopeptides are separately admitted into an Orbitrap analyzer with the appropriate injection times. We test the reproducibility of our assay by determining Rab10-Thr73 phosphorylation stoichiometry in neutrophils of LRRK2 mutation carriers before and after LRRK2 inhibition. Compared with healthy controls, the PD predisposing mutation carriers LRRK2 G2019S and VPS35 D620N display 1.9-fold and 3.7-fold increased pRab10 levels, respectively. Our generic MS-based assay further establishes the relevance of pRab10 as a prognostic PD marker and is a powerful tool for determining LRRK2 inhibitor efficacy and for stratifying PD patients for LRRK2 inhibitor treatment.

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Language Deficits as a Preclinical Window into Parkinson’s Disease: Evidence from Asymptomatic Parkin and Dardarin Mutation Carriers

Journal of the International Neuropsychological Society ◽

10.1017/s1355617716000710 ◽

2017 ◽

Vol 23 (2) ◽

pp. 150-158 ◽

Cited By ~ 23

Author(s):

Adolfo M. García ◽

Lucas Sedeño ◽

Natalia Trujillo ◽

Yamile Bocanegra ◽

Diana Gomez ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Executive Functions ◽

Language Processing ◽

Memory Load ◽

Analysis Of Covariance ◽

Mutation Carriers ◽

Language Measures ◽

Asymptomatic Individuals ◽

Processing Mechanisms

AbstractObjectives:The worldwide spread of Parkinson’s disease (PD) calls for sensitive and specific measures enabling its early (or, ideally, preclinical) detection. Here, we use language measures revealing deficits in PD to explore whether similar disturbances are present in asymptomatic individualsat riskfor the disease.Methods:We administered executive, semantic, verb-production, and syntactic tasks to sporadic PD patients, genetic PD patients with PARK2 (parkin) or LRRK2 (dardarin) mutation, asymptomatic first-degree relatives of the latter with similar mutations, and socio-demographically matched controls. Moreover, to detectsui generislanguage disturbances, we ran analysis of covariance tests using executive functions as covariate.Results:The two clinical groups showed impairments in all measures, most of which survived covariation with executive functions. However, the key finding concerned asymptomatic mutation carriers. While these subjects showed intact executive, semantic, and action-verb production skills, they evinced deficits in a syntactic test with minimal working memory load.Conclusions:We propose that thissui generisdisturbance may constitute a prodromal sign anticipating eventual development of PD. Moreover, our results suggest that mutations on specific genes (PARK2 and LRRK2) compromising basal ganglia functioning may be subtly related to language-processing mechanisms. (JINS, 2017,23, 150–158)

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