Exhaustion of mitochondrial and autophagic reserve may contribute to the development of LRRK2G2019S-Parkinson's disease

Background: Mutations in leucine rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). Mitochondrial and autophagic dysfunction has been described as etiologic factors in different experimental models of PD. We aimed to study the role of mitochondria and autophagy in LRRK2(G2019S)-mutation, and its relationship with the presence of PD-symptoms. Methods: Fibroblasts from six non-manifesting LRRK2(G2019S)-carriers (NM-LRRK2(G2019S)) and seven patients with LRRK2(G2019S)-associated PD (PD-LRRK2(G2019S)) were compared to eight healthy controls (C). An exhaustive assessment of mitochondrial performance and autophagy was performed after 24-h exposure to standard (glucose) or mitochondrial-challenging environment (galactose), where mitochondrial and autophagy impairment may be heightened. Results: A similar mitochondrial phenotype of NM-LRRK2(G2019S) and controls, except for an early mitochondrial depolarization (54.14% increased, p=0.04), was shown in glucose. In response to galactose, mitochondrial dynamics of NM-LRRK2(G2019S) improved (-17.54% circularity, p=0.002 and +42.53% form factor, p=0.051), probably to maintain ATP levels over controls. A compromised bioenergetic function was suggested in PD-LRRK2(G2019S) when compared to controls in glucose media. An inefficient response to galactose and worsened mitochondrial dynamics (-37.7% mitochondria) elongation, p=0.053) was shown, leading to increased oxidative stress. Autophagy initiation (SQTSM/P62) was upregulated in NM-LRRK2(G2019S) when compared to controls (glucose +118.4%, p=0.014; galactose +114.44%, p=0.009,) and autophagosome formation increased in glucose media. Despite of elevated SQSTM1/P62 levels of PD-NMG2019S when compared to controls (glucose +226.14%, p=0.04; galactose +78.5%, p=0.02), autophagosome formation was deficient in PD-LRRK2(G2019S) when compared to NM-LRRK2(G2019S) (-71.26%, p=0.022). Conclusions: Enhanced mitochondrial performance of NM-LRRK2(G2019S) in mitochondrial-challenging conditions and upregulation of autophagy suggests that an exhaustion of mitochondrial bioenergetic and autophagic reserve, may contribute to the development of PD in LRRK2(G2019S) mutation carriers.