Abstract
The G2019S mutation in the multidomain protein leucine-rich repeat kinase 2 (LRRK2) is one of the most frequently identified genetic causes of Parkinson’s disease (PD). Clinically, LRRK2(G2019S) carriers with PD and idiopathic PD patients have a very similar disease with brainstem and cortical Lewy pathology (α-synucleinopathy) as histopathological hallmarks. Some patients have Tau pathology. Enhanced kinase function of the LRRK2(G2019S) mutant protein is a prime suspect mechanism for carriers to develop PD but observations in LRRK2 knock-out, G2019S knock-in and kinase-dead mutant mice suggest that LRRK2 steady-state abundance of the protein also plays a determining role. One critical question concerning the molecular pathogenesis in LRRK2(G2019S) PD patients is whether α-synuclein (aSN) has a contributory role. To this end we generated mice with high expression of either wildtype or G2019S mutant LRRK2 in brainstem and cortical neurons. High levels of these LRRK2 variants left endogenous aSN and Tau levels unaltered and did not exacerbate or otherwise modify α-synucleinopathy in mice that co-expressed high levels of LRRK2 and aSN in brain neurons. On the contrary, in some lines high LRRK2 levels improved motor skills in the presence and absence of aSN-transgene-induced disease. Therefore, in many neurons high LRRK2 levels are well tolerated and not sufficient to drive or exacerbate neuronal α-synucleinopathy.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative movement disorder with clinical features including bradykinesia, rigidity and resting tremor
PD histopathological hallmarks are the loss of dopaminergic neurons in the substantia nigra and Lewy pathology
Polymorphic variants of genes including SNCA, leucine-rich repeat kinase-2 (LRRK2) and microtubuleassociated protein Tau (MAPT) have emerged as susceptibility factors associated with an increased risk to develop PD [14,15,16,17,18]
Summary
Parkinson’s disease (PD) is a common neurodegenerative movement disorder with clinical features including bradykinesia, rigidity and resting tremor. We experimentally approached this question differently by generating double transgenic mice co-expressing under the control of mouse Thy1-regulatory sequences high levels of aSN and LRRK2 in a large population of both forebrain and brainstem neurons.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
