Parkinson’s disease (PD) is the most common movement disorder and is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Dominantly inherited missense mutations in the leucine-rich repeat kinase 2 (Lrrk2) gene are the most common cause of both familial and sporadic PD, highlighting the importance of LRRK2 in PD pathogenesis (Paisán-Ruíz et al., 2004; Shen, 2004; Zimprich et al., 2004; Gilks et al., 2005; Lesage et al., 2007; Kluss et al., 2019; Shu et al., 2019; Mata et al., 2005a; Mata et al., 2005b; Zabetian et al., 2005; Hatano et al., 2014; Takanashi et al., 2018; Nichols et al., 2005; Di Fonzo et al., 2005; Hernandez et al., 2005; Kachergus et al., 2005). LRRK2 is a large protein of 2527 amino acid residues containing multiple functional domains, including several leucine-rich repeats (LRRs), a GTPase-like domain of Ras-of-complex (Roc), a C-terminal of Roc (COR) domain, and a serine/threonine MAPKKK-like kinase domain. LRRK1, a homolog of LRRK2, belongs to the evolutionarily conserved Roco protein family and contains similar LRRs, Roc, COR, and kinase domains (Bosgraaf and Van Haastert, 2003; Marín, 2006; Marín, 2008). LRRK proteins are broadly expressed, with LRRK2 being most abundant in the kidney (Biskup et al., 2007). While most PD mutations are found in LRRK2, rare variants in the Roc, COR, and kinase domains of LRRK1 have been reported and may be associated with PD (Schulte et al., 2014). Furthermore, the Roc-COR domain of LRRK2 forms dimers and exhibits conventional Ras-like GTPase properties, and the R1441/C/G/H and I1371V mutations destabilize dimer formation and decrease GTPase activity (Deng et al., 2008; Mills et al., 2018). Recent high-resolution cryoEM structural studies of full-length LRRK2 demonstrated its existence as dimers and pathogenic mutations such as R1441/C/G/H and Y1699I at the Roc-COR interface, whereas the G2910S mutant is structurally similar to the wild-type LRRK2 (Myasnikov et al., 2021).

Previous genetic studies demonstrated that LRRK2 plays essential roles in the autophagy-lysosomal pathway (Tong et al., 2010; Tong et al., 2012; Herzig et al., 2011; Tian et al., 2021). Consistent with high levels of LRRK2 expression in kidneys, Lrrk2^-/- mice develop age-dependent phenotypes in the kidney, including autophagy-lysosomal impairments and increases in α-synuclein, apoptosis, and inflammatory responses (Tong et al., 2010; Tong et al., 2012; Tong and Shen, 2012). It has also been reported that LRRK2 is important for maintaining lung homeostasis, and Lrrk2 deficiency results in impaired autophagy in alveolar type II epithelial cells (Tian et al., 2021). It was proposed that the lack of brain phenotypes in Lrrk2^-/- mice might be due to the presence of LRRK1, which could compensate functionally in the absence of LRRK2 (Tong et al., 2010; Tong et al., 2012). Indeed, Lrrk double knockout (DKO) mice develop an age-dependent, progressive loss of DA neurons in the SNpc, beginning at 14 months of age (Giaime et al., 2017). However, Lrrk DKO mice also exhibit lower body weight and earlier mortality, raising the possibility that DA neurodegeneration in aged Lrrk germline DKO mice may be secondary to poor health.

In this study, we investigate whether LRRK2 and its functional homolog LRRK1 play an essential, intrinsic role in DA neurons through the development of DA neuron-specific Lrrk conditional DKO (cDKO) mice using the Slc6a3-Cre knockin (KI) allele, in which Cre recombinase is expressed under the control of the endogenous promoter of the dopamine transporter gene Slc6a3. We first generated and confirmed floxed Lrrk1 and Lrrk2 mice, and then crossed them with the CMV-Cre deleter to create germline deletions of the floxed Lrrk1 and Lrrk2 alleles, followed by northern and western analyses to confirm the absence of Lrrk1 and Lrrk2 mRNAs, as well as LRRK1 and LRRK2 proteins in the respective homozygous deleted mutant mice. We also crossed a GFP reporter mouse with Slc6a3-Cre KI mice and confirmed that Cre-mediated recombination occurs in most, if not all, DA neurons in the SNpc and is restricted to DA neurons. We then crossed these thoroughly validated floxed Lrrk1 and Lrrk2 mice with Slc6a3-Cre KI mice to generate DA neuron-restricted Lrrk cDKO mice and further confirmed the reduction of LRRK1 and LRRK2 in dissected ventral midbrains of Lrrk cDKO mice. While DA neuron-restricted Lrrk cDKO mice of both sexes exhibit normal mortality and body weight, they develop age-dependent loss of DA neurons in the SNpc, as demonstrated by the progressive reduction of TH+ DA neurons or NeuN+ neurons in the SNpc of cDKO mice at the ages of 20 and 24 months but not at 15 months. Moreover, DA neurodegeneration is accompanied with increases in apoptotic DA neurons and elevated microgliosis in the SNpc as well as decreases in DA terminals in the striatum, and is preceded by impaired motor coordination. Interestingly, quantitative electron microscopy (EM) analysis showed a similar number of electron-dense vacuoles in SNpc neurons of Lrrk cDKO mice relative to controls, in contrast to age-dependent increases in vacuoles in SNpc neurons of Lrrk germline DKO mice (Giaime et al., 2017; Huang et al., 2022). These findings provide the unequivocal evidence for the importance of LRRK in DA neurons and raise the possibility that LRRK2 mutations may impair this crucial physiological function, leading to DA neurodegeneration in PD.

LRRK2 mutations are linked to familial PD and are also associated with sporadic PD with the G2019S mutation being the most common but exhibiting lower penetrance and higher age of onset (e.g., 74% at age 79) (Healy et al., 2008). Despite the importance of LRRK2 in PD pathogenesis, whether LRRK2 mutations cause DA neurodegeneration via a loss- or gain-of-function mechanism remains unresolved, even though the distinction between these two pathogenic mechanisms is critical for directing LRRK2-based PD therapeutic development. Neither Lrrk2-deficient mice nor Lrrk2 R1441C and G2019S KI mice develop dopaminergic neurodegeneration (Tong et al., 2010; Tong et al., 2009; Yue et al., 2015). It was proposed that the lack of brain phenotypes in Lrrk2-null mice might be due to the presence of LRRK1 (Tong et al., 2010; Tong et al., 2012), which is broadly expressed in the brain including the midbrain (https://www.proteinatlas.org/ENSG00000154237-LRRK1/brain). Indeed, germline deletions of Lrrk2 and Lrrk1 result in an age-dependent loss of DA neurons and increases in apoptosis and microgliosis in the SNpc of Lrrk DKO mice (Giaime et al., 2017; Huang et al., 2022). However, the pleiotropic roles of LRRK1 and LRRK2 in the kidney (Tong et al., 2010; Tong et al., 2012; Tong and Shen, 2012), lung (Tian et al., 2021), and bone (Xing et al., 2013; Guo et al., 2017), and the observed earlier mortality and lower body weight in Lrrk DKO mice raised the possibility that DA neurodegeneration in Lrrk DKO mice may be due to poor health.

To address this question, we generated floxed Lrrk1 and Lrrk2 mice (Figure 1Figure 1—figure supplements 1–8) and DA neuron-specific Lrrk cDKO mice using the Slc6a3-Cre KI allele (Bäckman et al., 2006) to delete floxed Lrrk1 and Lrrk2 regions selectively in DA neurons (Figure 2). Using a GFP reporter line, we found that Slc6a3-Cre drives Cre-mediated recombination in almost all DA neurons in the SNpc. Unlike germline DKO mice (Giaime et al., 2017), DA neuron-specific Lrrk cDKO mice exhibit normal body weight and mortality during mouse lifespan. Importantly, Lrrk cDKO mice develop an age-dependent, progressive DA neurodegeneration, as evidenced by the normal number of DA neurons at the age of 15 months and the progressive reduction of DA neurons in the SNpc at the ages of 20 and 24 months (Figure 3), accompanied with increases in apoptotic DA neurons in the SNpc (Figure 4) and decreases in DA terminals in the striatum (Figure 5), whereas the number of noradrenergic neurons in the LC is unchanged, consistent with the lack of Cre-mediated recombination in the LC by Slc6a3-Cre (Figure 6). Moreover, Lrrk cDKO mice exhibit impaired performance in a narrow beam walk, a behavioral paradigm sensitive to altered motor coordination (Figure 9). Furthermore, microgliosis is elevated in the SNpc of Lrrk cDKO mice, even though LRRK expression in microglia is unaffected in these mice, suggesting a cell-extrinsic microglial response to pathophysiological changes in DA neurons (Figure 8). The molecular mechanism by which LRRK supports cell-autonomous DA neuron survival is unknown. Single-cell RNA sequencing of dissected ventral midbrains may permit identification of genes and pathways that are selectively altered in DA neurons of Lrrk cDKO mice before and after the onset of DA neurodegeneration.

Interestingly, quantitative EM analysis showed similar numbers of electron-dense vacuoles in the SNpc of Lrrk cDKO and control mice at 25 months of age (Figure 7), in contrast to age-dependent increases in vacuoles in the SNpc of Lrrk DKO mice (Giaime et al., 2017; Huang et al., 2022), suggesting non-DA neurons (e.g., microglia), in which LRRK expression is unaffected in DA neuron-specific Lrrk cDKO mice but is absent in germline DKO mice, may contribute to this phenotypic difference. Development of microglia- and/or astrocyte-specific Lrrk cDKO mice would permit further dissection of cell-autonomous and non-cell-autonomous roles of LRRK in DA neuron survival and determine whether glial LRRK plays a more important role in the regulation of the autophagy-lysosomal pathway and protein turnover. It would also be interesting to test whether reducing LRRK expression or function affects accumulation and aggregation of human mutant α-synuclein and tau in the aging brain, as both Lewy bodies and tauopathies are associated with PD patients carrying LRRK2 mutations (Zimprich et al., 2004).

The toxic gain-of-function pathogenic mechanism was initially proposed based on in vitro kinase assays using recombinant mutant LRRK2, which showed that R1441C and G2019S resulted in increases in autophosphorylation and phosphorylation of a generic substrate (West et al., 2005). Subsequent biochemical studies further reported that LRRK2 mutations (e.g., R1441C/G, G2019S) enhanced kinase activity, leading to elevated levels of pSer1292-LRRK2 (Sheng et al., 2012) as well as pT73-Rab10 and pS106-Rab12 (Steger et al., 2016). While these biochemical changes are excellent biomarkers of LRRK2 mutations, there is no experimental evidence showing that increased phosphorylation of LRRK2 substrates drives DA neurodegeneration.

The loss-of-function pathogenic mechanism was prompted by mouse knockout findings showing that germline inactivation of the Lrrk genes results in age-dependent loss of DA neurons in the SNpc and DA terminals in the striatum (Giaime et al., 2017; Huang et al., 2022). The current study demonstrated a cell-intrinsic role of LRRK in support of DA neuron survival in the SNpc of the aging brain, providing an unequivocal genetic evidence of an essential, cell-autonomous requirement of LRRK in DA neurons. While most transgenic mice overexpressing mutant LRRK2 did not produce neurodegeneration or DA neuron loss (Li et al., 2009; Lin et al., 2009; Li et al., 2010; Melrose et al., 2010; Daher et al., 2012; Tsika et al., 2014; Liu et al., 2015; Mikhail et al., 2015; Xiong et al., 2017), two studies reported that overexpression of LRRK2 G2019S but not R1441C resulted in DA neurodegeneration (Ramonet et al., 2011; Xiong et al., 2018). These transgenic mouse results are intriguing as R1441C is a more potent causative mutation (highly penetrant, in a critical amino acid residue that harbors three distinct PD mutations), whereas G2019S is known to be a weaker mutation with a lower penetrance and an older age of disease onset.

It remains possible that the relevant physiological role of LRRK in the protection of DA neuron survival during aging may be irrelevant to how LRRK2 mutations cause DA neurodegeneration and PD. Two reports of genomic database analysis suggested that loss-of-function Lrrk2 and Lrrk1 variants are not associated with PD (Whiffin et al., 2020; Blauwendraat et al., 2018), which were sometimes taken as conclusive evidence for LRRK2 mutations not being loss of function. One study was a predictive analysis using several available sequencing databases (141,456 individuals sequenced in the Genome Aggregation Database, 49,960 exome-sequenced individuals from the UK Biobank, and more than 4 million participants in the 23andMe genotyped dataset), and the authors cautiously stated that heterozygous predicted loss-of-function variants are not strongly associated with PD (Whiffin et al., 2020). Another study analyzed next-generation sequencing data from 11,095 PD patients and 12,615 controls, and found that Lrrk1 loss-of-function variants were identified in 0.205% PD cases and 0.139% of controls, whereas Lrrk2 loss-of-function variants were found in 0.117% of PD cases and 0.087% of controls (Blauwendraat et al., 2018). In contrast to linkage studies of large pedigrees with mutations segregating completely with the disease but being absent among control populations, these genomic database analysis studies are considerably weaker with the results suggestive but highly inconclusive. For example, while the occurrence of these loss-of-function variants among PD patients is not statistically different from those among control populations, a larger sample size may change this outcome. Furthermore, such sequencing data tend to be from highly heterogeneous populations, contributing to further complexity. Moreover, it is quite possible that haploinsufficiency or heterozygous complete loss-of-function mutations are not sufficient to cause the disease; rather a dominant negative mechanism, coupled with loss of function missense mutations, may be at play, reducing overall protein function further, especially if dimers are the functional entities. Therefore, these studies are interesting but inconclusive as to whether loss-of-function mutations in LRRK2 or LRRK1 cause or do not cause PD.

Genetically, it is well known that missense mutations may gain a toxic function or may cause a partial loss of function in cis and a dominant negative inhibition of wild-type protein in trans, further reducing its function. Missense mutations in the PSEN genes linked to familial Alzheimer’s disease are good examples of such a loss-of-function coupled with a dominant negative mechanism (Shen and Kelleher, 2007; Heilig et al., 2010; Heilig et al., 2013; Zhou et al., 2017; Watanabe and Shen, 2017; Sun et al., 2017; Kelleher and Shen, 2017). While PD-linked Lrrk2 mutations are mostly dominantly inherited missense mutations, though homozygous R1441H carriers have been reported (Takanashi et al., 2018), variants in LRRK1 have also been reported with inconclusive pathogenicity (Schulte et al., 2014; Haugarvoll et al., 2007). The notion that mutant LRRK2 may act in a dominant negative manner to inhibit the activity of wild-type LRRK2 is supported by structural and functional studies of LRRK2 as homodimers or heterodimers with LRRK1 (Deng et al., 2008; Myasnikov et al., 2021; Zhang et al., 2019; Greggio et al., 2008; Sen et al., 2009; Jorgensen et al., 2009; Dachsel et al., 2010). Furthermore, LRRK2 G2385R variant, a risk factor of PD (Farrer et al., 2007; Kim et al., 2010; An et al., 2008; Xie et al., 2014), has been reported as a partial loss-of-function mutation (Rudenko et al., 2012; Carrion et al., 2017). Future studies are needed to reconcile the biochemical findings of elevated kinase activity by LRRK2 mutations and the genetic findings of an essential physiological role of LRRK in DA neuron survival, and to determine whether LRRK2 mutations impair this relevant physiological function in protecting DA neurons while increasing kinase activity.

All data generated or analysed during this study are included in the manuscript and supporting files; source data files have been provided for key findings shown in Figures 1, 3, 4, 8, and 9.

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Author details

1. Jongkyun Kang

   Department of Neurology, Brigham and Women’s Hospital, Boston, United States

   Contribution

   Data curation, Validation, Investigation, Methodology, Writing – original draft, Writing – review and editing, Western analysis of deleted LRRK1 and LRRK2 mice as well as cDKO mice; quantitative histological and EM analyses of the SNpc, including independent quantification of TH+ neurons in the SNpc and quantification of TH+ terminals in the striatum

   Contributed equally with

   Guodong Huang

   Competing interests

   No competing interests declared

2. Guodong Huang

   Department of Neurology, Brigham and Women’s Hospital, Boston, United States

   Contribution

   Data curation, Investigation, Methodology, Writing – original draft, Northern analysis and RT-PCR followed by sequencing of floxed and deleted LRRK1 and LRRK2 mice; quantitative histological and EM analyses of the SNpc, including independent quantification of TH+ neurons in the SNpc and quantification of TH+ terminals in the striatum; independent behavioral validation

   Contributed equally with

   Jongkyun Kang

   Competing interests

   No competing interests declared

3. Long Ma

   Department of Neurology, Brigham and Women’s Hospital, Boston, United States

   Contribution

   Data curation, Investigation, Methodology, Generated the targeting vectors and performed ES cell experiments and Southern blotting for LRRK1

   Competing interests

   No competing interests declared

4. Youren Tong

   Department of Neurology, Brigham and Women’s Hospital, Boston, United States

   Contribution

   Data curation, Investigation, Methodology, Generated the targeting vectors and performed ES cell experiments and Southern blotting for LRRK2

   Competing interests

   No competing interests declared

5. Anu Shahapal

   Department of Neurology, Brigham and Women’s Hospital, Boston, United States

   Contribution

   Data curation, Investigation, Methodology, Writing – review and editing, Performed behavioral analysis

   Competing interests

   No competing interests declared

6. Phoenix Chen

   Department of Neurology, Brigham and Women’s Hospital, Boston, United States

   Contribution

   Data curation, Investigation, Methodology, Performed the GFP reporter analysis of DAT-Cre mice in the SNpc and the LC

   Competing interests

   No competing interests declared

7. Jie Shen

   1. Department of Neurology, Brigham and Women’s Hospital, Boston, United States
   2. Program in Neuroscience, Harvard Medical School, Boston, United States

   Contribution

   Conceptualization, Supervision, Funding acquisition, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   jshen@bwh.harvard.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1160-7118

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