The progression rate in subjects with PD who carried LRRK2 mutation was slightly slower (~0.170 points/month) than that in PD subjects without the mutation (~0.222 points/month).
Mutations in the gene encoding leucine-rich repeat kinase 2 (<i>LRRK2</i>), such as the G2019S mutation, are the most common cause of familial Parkinson's disease (PD).
The objective of this study was to investigate alterations in urinary phospholipids as biomarkers of LRRK2 mutations and Parkinson's disease status/phenotypes.
1.Available evidence confirms that the LRRK2 variant rs34637584 is associated with less cognitive impairment in people with PD.2.GBA variants rs76763715 and rs421016 are associated with more severe cognitive impairment in people with PD.3.The GBA variants rs76763715, rs421016, rs387906315 and rs80356773 have been significantly associated with the onset of depressive symptoms in PD.
The G2019S substitution in the kinase domain of LRRK2 (LRRK2<sup>G2019S</sup>) is the most prevalent mutation associated with Parkinson's disease (PD).
In light of recent reports of disease-mirroring EMV molecular signatures, the present study profiled two EMVs from different Parkinson's disease (PD) tissue sources: (a) neural progenitor cells derived from an endogenous adult stem/progenitor cell, called adult human neural progenitor (AHNP) cells, that we found to be pathological when isolated from postmortem PD patients' substantia nigra; and (b) leucine-rich repeat kinase 2 (LRRK2) gene identified patient induced pluripotent stem cells (iPSCs), which were used to isolate EMVs and begin to characterize their cargoes.
The fact that a LRRK2 kinase inhibitor was capable of preventing the neuropathological and endolysosomal abnormalities observed in human iPD suggests that LRRK2 inhibitors may have broad therapeutic utility in iPD, not only in those who carry a LRRK2 mutation.
Here, we review the current understanding of the mechanisms by which LRRK2 regulates lysosomal-based degradative pathways in neuronal and non-neuronal cells and discuss the impact of pathogenic PD mutations in contributing to lysosomal dyshomeostasis.
In preparation for upcoming precision medicine-designed clinical trials for GBA and LRRK2, we evaluated movement disorders specialists' current practice, knowledge, attitudes, and barriers to genetic testing in PD.
Interestingly, α-synuclein and LRRK2, key proteins involved in PD, function in different steps of the E-L pathway and target their components to induce disease pathogenesis.
G2019SLRRK2 mutation displays increased mitophagy due to the activation of class III HDACs whereas idiopathic PD exhibits downregulation of clearance of defective mitochondria.
Finally, we assessed the association of neuropathology with clinical features in LRRK2 mutation carriers and idiopathic individuals and find that LRRK2PD shares clinical and pathological features of idiopathic PD.
Our study uncovers vitamin B<sub>12</sub> as a novel class of LRRK2 kinase modulator with a distinct mechanism, which can be harnessed to develop new LRRK2-based PD therapeutics in the future.
These findings demonstrate an important role for LRRK2 protein in regulation of mitochondrial clearance by the lysosomes, which is hampered in PD with the G2019S mutation.
For instance, late and early onset PD associated to mutations in Leucine-rich repeat kinase 2 (<i>LRRK2</i>) and Parkin (<i>PRKN</i>) genes, responsible for the most frequent dominant and recessive inherited forms of PD, respectively, have emerged as promising examples of disease due to their established role in commanding bioenergetic and autophagic balance.