title: High LRRK2 levels fail to induce or exacerbate neuronal alpha-synucleinopathy in mouse brain.
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.
authors.affiliation: Department of Neuroscience, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Herzig
authors.forename: Michael
authors.initials: M
authors.lastname: Bidinosti
authors.forename: Tatjana
authors.initials: T
authors.lastname: Schweizer
authors.forename: Thomas
authors.initials: T
authors.lastname: Hafner
authors.forename: Christine
authors.initials: C
authors.lastname: Stemmelen
authors.forename: Andreas
authors.initials: A
authors.lastname: Weiss
authors.forename: Simone
authors.initials: S
authors.lastname: Danner
authors.forename: Nella
authors.initials: N
authors.lastname: Vidotto
authors.forename: Daniela
authors.initials: D
authors.lastname: Stauffer
authors.forename: Carmen
authors.initials: C
authors.lastname: Barske
authors.forename: Franziska
authors.initials: F
authors.lastname: Mayer
authors.forename: Peter
authors.initials: P
authors.lastname: Schmid
authors.forename: Giorgio
authors.initials: G
authors.lastname: Rovelli
authors.forename: P Herman
authors.initials: PH
authors.lastname: van der Putten
authors.forename: Derya R
authors.initials: DR
authors.lastname: Shimshek
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D005260:Female; D017403:In Situ Hybridization; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases