LRRK2 is considered a very attractive target for therapeutic development, and, in fact, several potent and selective LRRK2 kinase inhibitors have been developed and are considered one of the major disease-modifying therapeutic strategies for PD ( Taymans and Greggio, 2016). The toxic effects of LRRK2 G2019S on dopaminergic (DA) neurons are believed to result from increased kinase activity compared to the WT protein ( West et al., 2005). The Gly2019Ser (G2019S) substitution in the LRRK2 kinase domain is the most common mutation, accounting for 5-6% of familial PD and 1-2% of sporadic cases ( Correia Guedes et al., 2010).

Among the 20 identified LRRK2 mutations, six of them have been demonstrated to be pathogenic and causing toxicity in cellular and animal models ( Rudenko and Cookson, 2014). The LRRK2 gene encodes a large, multidomain protein with kinase activity.

LRRK2 mutations are the most common genetic cause of both familial and sporadic PD ( Paisan-Ruiz et al., 2004 Zimprich et al., 2004). LRRK2 and SNCA) as risk factors for the development of non-familial PD ( Cookson, 2015 Lill et al., 2012 Ross et al., 2011 Satake et al., 2009 Simon-Sanchez et al., 2009), suggesting that shared biological pathways drive disease pathogenesis in both hereditary and sporadic cases ( Cookson, 2015 Kluss et al., 2019). Of interest, genome-wide association studies (GWAS) have linked variations in some of these genes (e.g. Although most PD cases are sporadic, resulting from a complex interaction of environmental and genetic factors, rare familial forms of the disease also exist and are caused by mutations in genes such as leucine-rich repeat kinase 2 ( LRRK2), О±-synuclein ( SNCA), PARK2 (also known as PRKN), PARK7 or PTEN-induced kinase 1 ( PINK1) ( Kalia and Lang, 2015 Martin et al., 2011). The histopathological hallmark of PD is the degeneration and loss of dopaminergic neurons of the substantia nigra in the ventral midbrain ( Fearnley and Lees, 1991 Lees et al., 2009). Parkinson's disease (PD) is a progressive neurodegenerative disease for which no preventative or curative treatments exist. In addition, our model could be applied to high-throughput and phenotypic screenings for the identification of novel PD therapeutics. This model could be used to elucidate G2019S LRRK2-mediated dopaminergic neural dysfunction and to identify novel molecular targets for disease intervention. We show that these cells can differentiate into dopaminergic-like neurons and that expression of mutant LRRK2 causes a range of different phenotypes, including reduced nuclear eccentricity, altered mitochondrial and lysosomal morphologies, and increased dopaminergic cell death. In order to combine biological relevance and throughput, we have developed a PD model in Lund human mesencephalic (LUHMES) cell-derived dopaminergic neurons by overexpressing wild-type (WT) and G2019S LRRK2 proteins. However, current cellular PD models either lack physiological relevance to dopaminergic neurons or are too complex and costly for scaling up the production process and for screening purposes. Cellular models are commonly used for testing novel potential neuroprotective compounds. As no treatment is available for this devastating disease, developing new therapeutic strategies is of foremost importance. Mutations in leucine-rich repeat kinase 2 ( LRRK2) are the most common genetic cause of late-onset PD identified to date, with G2019S being the most frequent LRRK2 mutation, which is responsible for up to 1-2% of sporadic PD and up to 6% of familial PD cases.

Parkinson's disease (PD) is a fatal neurodegenerative disorder that is primarily caused by the degeneration and loss of dopaminergic neurons of the substantia nigra in the ventral midbrain.

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