LAUSR

Autosomal dominant mutations in Leucine Rich Repeat Kinase 2 (LRRK2) underlie the most common cause of familial Parkinson’s disease (PD) and have also been associated with sporadic cases. However, LRRK2 mutation knockin and LRRK2 knockout (KO) animal models do not show dopaminergic neurodegeneration or a-synuclein aggregation in the brain, 2 of the main pathological hallmarks in PD. To address whether Leucine Rich Repeat Kinase 1 (LRRK1), the homologue of LRRK2, explains the lack of face validity in LRRK2 animal models by a compensatory mechanism, Giaime et al. generated LRRK1/LRRK2 double knockout (LRRK DKO) mice. In contrast with LRRK1/LRRK2 single KO mice, LRRK DKO mice exhibit drastically decreased body weight and unexplained mortality with cataracts at 16 months of age. From the perspective of PD, the first exciting findings came from neuronal counts in brain areas affected in PD. LRRK DKO mice show a small but significant loss ( 22%) of dopaminergic neurons in the substantia nigra pars compacta (SNpc) at 15 months, but not younger ages. A loss of both dopaminergic and medium spiny neurons was observed in the striatum at 15 months, whereas the number of neurons in the cerebral cortex and cerebellum remained unaltered. The levels of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were also significantly reduced in the striatum. Together, these data suggest a specific, age-dependent neurodegeneration. Interestingly, this neurodegeneration is accompanied by increased apoptotic markers in the SNpc and striatum of the LRRK DKO mice. In addition, the striatum and SNpc of LRRK DKO but not LRRK1/LRRK2 single KO mice showed increased immunostaining for a-synuclein, and Western blot analysis revealed increases in monomeric and high-molecular-weight a-synuclein in the striatum. Finally, the autophagic marker p62 was increased in the multiple brain areas. Further electron microscopic structural analysis revealed the presence of autophagic structures in the SNpc and striatum of the LRRK DKO mice. Remarkably, this increase in autophagic structures was observed at 10 months and therefore preceded neurodegeneration, indicating autophagy may contribute early to neurodegeneration. The LRRK DKO is an exciting model, but it has a few limitations. First, motor impairments in LRRK DKO mice were not reported, and the young mortality of LRRK DKO mice at 16 months may limit investigation of the effects of aging on brain pathophysiology. The precise underlying mechanism of age-dependent dopaminergic neurodegeneration by LRRK1/LRRK2 deficiency is unknown. In addition, pathogenic LRRK2 mutations are thought to be gain-offunction mutations; thus, although a knockout model may be enlightening within the context of understanding LRRK biology, the direct relevance of such a model to disease should be interpreted with this opposite mode of action in mind.