Regulation of physiologic actions of LRRK2: focus on autophagy.
BACKGROUND
Mutations in LRRK2 are associated with familial and sporadic Parkinson's disease (PD). Subjects with PD caused by LRRK2 mutations show pleiotropic pathology that can involve inclusions containing α-synuclein, tau or neither protein. The mechanisms by which mutations in LRRK2 lead to this pleiotropic pathology remain unknown.


OBJECTIVE
To investigate mechanisms by which LRRK2 might cause PD.


METHODS
We used systems biology to investigate the transcriptomes from human brains, human blood cells and Caenorhabditis elegans expressing wild-type LRRK2. The role of autophagy was tested in lines of C. elegans expressing LRRK2, V337M tau or both proteins. Neuronal function was measured by quantifying thrashing.


RESULTS
Genes regulating autophagy were coordinately regulated with LRRK2. C. elegans expressing V337M tau showed reduced thrashing, as has been noted previously. Coexpressing mutant LRRK2 (R1441C or G2019S) with V337M tau increased the motor deficits. Treating the lines of C. elegans with an mTOR inhibitor that enhances autophagic flux, ridaforolimus, increased the thrashing behavior to the same level as nontransgenic nematodes.


CONCLUSIONS
These data support a role for LRRK2 in autophagy, raise the possibility that deficits in autophagy contribute to the pathophysiology of LRRK2, and point to a potential therapeutic approach addressing the pathophysiology of LRRK2 in PD.
Department of Pharmacology, Boston University School of Medicine, Boston, Mass 02118-2526, USA.
Andrew
A
Ferree
Maria
M
Guillily
Hu
H
Li
Katelyn
K
Smith
Aki
A
Takashima
Rachel
R
Squillace
Manfred
M
Weigele
James J
JJ
Collins
Benjamin
B
Wolozin
D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D017173:Caenorhabditis elegans; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008715:Methionine / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D014633:Valine / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism
D016875:tau Proteins; C515074:ridaforolimus; D008715:Methionine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D014633:Valine; D020123:Sirolimus