Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice

Winner, Beate; Melrose, HL; Zhao, Chen; Hinkle, KM; Yue, Mei; Kent, Caroline; Braithwaite, Adam; Ogholikhan, Sina; Aigner, Robert; Winkler, Jürgen; Farrer, Matthew J.; Gage, F. H.

doi:10.1016/j.nbd.2010.12.008

Cited by 171 publications

(173 citation statements)

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“…As reported by other investigators in different cell types [53][54][55][56][57][58][59], we also observed that the overexpression of LRRK2 G2019S results in shortened neuritic extensions. We explored potential molecular contributors to this pathogenic neuritic phenotype.…”

Section: Discussionsupporting

confidence: 91%

Development of Inducible Leucine-rich Repeat Kinase 2 (LRRK2) Cell Lines for Therapeutics Development in Parkinson's Disease

et al. 2013

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The pathogenic mechanism(s) contributing to loss of dopamine neurons in Parkinson's disease (PD) remain obscure. Leucine-rich repeat kinase 2 (LRRK2) mutations are linked, as a causative gene, to PD. LRRK2 mutations are estimated to account for 10 % of familial and between 1 % and 3 % of sporadic PD. LRRK2 proximate single nucleotide polymorphisms have also been significantly associated with idiopathic/sporadic PD by genome-wide association studies. LRRK2 is a multidomain-containing protein and belongs to the protein kinase super-family. We constructed two inducible dopaminergic cell lines expressing either human-LRRK2-wild-type or human-LRRK2-mutant (G2019S). Phenotypes of these LRRK2 cell lines were examined with respect to cell viability, morphology, and protein function with or without induction of LRRK2 gene expression. The overexpression of G2019S gene promoted 1) low cellular metabolic activity without affecting cell viability, 2) blunted neurite extension, and 3) increased phosphorylation at S910 and S935. Our observations are consistent with reported general phenotypes in LRRK2 cell lines by other investigators. We used these cell lines to interrogate the biological function of LRRK2, to evaluate their potential as a drug-screening tool, and to investigate screening for small hairpin RNA-mediated LRRK2 G2019S gene knockdown as a potential therapeutic strategy. A proposed LRRK2 kinase inhibitor (i.e., IN-1) decreased LRRK2 S910 and S935 phosphorylation in our MN9DLRRK2 cell lines in a dose-dependent manner. Lentivirus-mediated transfer of LRRK2 G2019S allele-specific small hairpin RNA reversed the blunting of neurite extension caused by LRRK2 G2019S overexpression. Taken together, these inducible LRRK2 cell lines are suitable reagents for LRRK2 functional studies, and the screening of potential LRRK2 therapeutics.

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Section: Discussionsupporting

confidence: 91%

Development of Inducible Leucine-rich Repeat Kinase 2 (LRRK2) Cell Lines for Therapeutics Development in Parkinson's Disease

et al. 2013

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“…Furthermore, LRRK2 is expressed in NSCs isolated from both the DG and SVZ of E18.5 mice. The LRRK2 protein may interact with the regulator of neurite outgrowth during embryonic neurogenesis, CRMP2 [77] and numerous studies have demonstrated that mutant LRRK2 overexpression decreases neurite length/outgrowth, while LRRK2 deficits result in an increase of neurite length and arborization [78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94]. Moreover, LRRK2 has been shown to bind Wnt signaling components (the DVL proteins) and play a role in the canonical Wnt/bcatenin signaling pathway, an important pathway for neurogenesis and in particular the development of DA neurons [83,95,96].…”

Section: Evidence For a Developmental Component Of Pd: Deregulated Emmentioning

confidence: 99%

“…Indeed, transgenic mice overexpressing the PD-associated human LRRK2 G2019S protein display a significant decrease in the number of proliferating (BrdU positive) cells in the adult DG, SVZ and RMS and decreased neurogenesis (BrdU and NeuN positive) and DA neurogenesis (BrdU, NeuN and TH positive) as well as decreased survival of newly generated neurons in the OB [86]. The LRRK2 G2019S mutation may contribute to the hippocampal and SVZ-related age-dependent non-motor symptoms via dysfunctions in the NSC pool and in their neural derivatives at early stages of maturation.…”

Section: Overexpression Of Mutated Lrrk2mentioning

confidence: 99%

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Grand

Gonzalez-Cano

Pavlou

et al. 2014

Cell. Mol. Life Sci.

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Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, nonmotor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/bcatenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PDrelated genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.

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“…This strategy could be useful in scenarios where proliferation itself has been reduced by the particular disease, like Parkinson disease. [84][85][86][87] In many diseases and injury, maturation and/or survival are also impaired. For differentiation, Ca v 1 voltage-gated Ca 2+ channels as well as other yet to be identified channels involved in maturation could be stimulated (e.g., Bay K8644) to enhance differentiation.…”

Section: Summary-targeting Specific Channels For Brain Repairmentioning

confidence: 99%