In recent years, numerous clinical trials for disease modification in Parkinson’s disease (PD) have failed, possibly because of a “one-size-fits all” approach. Alternatively, a precision medicine ...approach, which customises treatments based on patients’ individual genotype, may help reach disease modification. Here, we review clinical trials that target genetic forms of PD, i.e.,
GBA
-associated and
LRRK2
-associated PD. In summary, six ongoing studies which explicitely recruit
GBA
-PD patients, and two studies which recruit
LRRK2
-PD patients, were identified. Available data on mechanisms of action, study design, and challenges of therapeutic trials are discussed.
One of the greatest advances in Parkinson's disease (PD) research in the past two decades has been a better understanding of PD genetics. Of the many candidate genes investigated, the best studied ...include
and
. The authors review the key clinical features of these monogenic forms, as well as for the prevalent risk factor gene,
including the phenotype, clinical course, and treatment response. They also outline areas for future investigation: longitudinal studies of PD's clinical course, the identification of its premotor manifestations, and its specific mechanisms of pathogenicity.
Parkinson's disease (PD) is a common neurodegenerative disease whose pathological hallmark is the accumulation of intracellular α-synuclein aggregates in Lewy bodies. Lipid metabolism dysregulation ...may play a significant role in PD pathogenesis; however, large plasma lipidomic studies in PD are lacking. In the current study, we analyzed the lipidomic profile of plasma obtained from 150 idiopathic PD patients and 100 controls, taken from the 'Spot' study at Columbia University Medical Center in New York. Our mass spectrometry based analytical panel consisted of 520 lipid species from 39 lipid subclasses including all major classes of glycerophospholipids, sphingolipids, glycerolipids and sterols. Each lipid species was analyzed using a logistic regression model. The plasma concentrations of two lipid subclasses, triglycerides and monosialodihexosylganglioside (GM3), were different between PD and control participants. GM3 ganglioside concentration had the most significant difference between PD and controls (1.531±0.037 pmol/μl versus 1.337±0.040 pmol/μl respectively; p-value = 5.96E-04; q-value = 0.048; when normalized to total lipid: p-value = 2.890E-05; q-value = 2.933E-03). Next, we used a collection of 20 GM3 and glucosylceramide (GlcCer) species concentrations normalized to total lipid to perform a ROC curve analysis, and found that these lipids compare favorably with biomarkers reported in previous studies (AUC = 0.742 for males, AUC = 0.644 for females). Our results suggest that higher plasma GM3 levels are associated with PD. GM3 lies in the same glycosphingolipid metabolic pathway as GlcCer, a substrate of the enzyme glucocerebrosidase, which has been associated with PD. These findings are consistent with previous reports implicating lower glucocerebrosidase activity with PD risk.
Purpose of Review
GBA
mutations are the most common known genetic cause of Parkinson’s disease (PD). Its biological pathway may be important in idiopathic PD, since activity of the enzyme encoded by
...GBA
, glucocerebrosidase, is reduced even among PD patients without
GBA
mutations. This article describes the structure and function of
GBA
, reviews recent literature on the clinical phenotype of
GBA
PD, and suggests future directions for research, counseling, and treatment.
Recent Findings
Several longitudinal studies have shown that
GBA
PD has faster motor and cognitive progression than idiopathic PD and that this effect is dose dependent. New evidence suggests that
GBA
mutations may be important in multiple system atrophy. Further, new interventional studies focusing on
GBA
PD are described. These studies may increase the interest of PD patients and caregivers in genetic counseling.
Summary
GBA
mutation status may help clinicians estimate PD progression, though mechanisms underlying
GBA
and synucleinopathy require further understanding.
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