Published in:
Open Access 01-12-2018 | Research
Exhaustion of mitochondrial and autophagic reserve may contribute to the development of LRRK2 G2019S -Parkinson’s disease
Published in: Journal of Translational Medicine | Issue 1/2018
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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% mitochondrial 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-NM
G2019S
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.