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Precision medicine in Parkinson's disease patients with LRRK2 and GBA risk variants-Let's get even more personal

Translational Neurodegeneration 2020年第4期9卷 499-508页

作者： Christian U.von Linstow Ziv Gan-Or Patrik Brundin Center for Neurodegenerative Science Van Andel InstituteGrand RapidsMI 49503USA Montreal Neurological Institute McGill UniversityMontrealQC H3A 2B4Canada Department of Human Genetics McGill UniversityMontrealQC H3A 0C7Canada Department of Neurology and Neurosurgery McGill UniversityMontrealQC H3A 2B4Canada

Parkinson's disease(PD)is characterized by motor deficits and a wide variety of non-motor *** age of onset,rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual ***,the loss of substantia nigra dopaminergic neurons is a key feature of *** vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions,but there is also great variability in the neuropathology between *** the dopamine replacement therapies can reduce motor symptoms,current therapies do not modify the disease *** clinical trials using a wide variety of approaches have failed to achieve disease *** has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials,and that it is unlikely that a single treatment will be effective in all *** medicine,using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD,has been suggested as a way *** patients can be stratified according to whether they carry one of the risk variants associated with elevated PD *** this review we assess current clinical trials targeting two enzymes,leucine-rich repeat kinase 2(LRRK2)and glucocerebrosidase(GBA),which are encoded by two most common PD risk *** the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood,we ask if these precision medicinebased intervention strategies will prove"precise"or"personalized"enough to modify the disease process in PD *** also consider at what phases of the disease that such strategies might be effective,in light of the genes being primarily associated with the risk of developing disease in the first place,and less clearly linked to the rate of disease ***,we critically evaluate the notion that therapies target

关键词： Parkinson's disease Precision medicine Personalized medicine Glucocerebrosidase GCase leucine-rich repeat kinase-2 Dopamine PD drug trials PD risk variants

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