The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of Parkinson's disease (PD) and results in age-related dopamine neuron loss and locomotor dysfunction in Drosophila melanogaster through an aberrant increase in bulk neuronal protein synthesis. Under nonpathologic conditions, protein synthesis is tightly controlled by metabolic regulation. Whether nutritional and metabolic influences on protein synthesis can modulate the pathogenic effect of LRRK2 on protein synthesis and thereby impact neuronal loss is a key unresolved question. Here, we show that LRRK2 G2019S-induced neurodegeneration is critically dependent on dietary amino acid content in Drosophila studies with both sexes. Low dietary amino acid concentration prevents aberrant protein synthesis and blocks LRRK2 G2019S-mediated neurodegeneration in Drosophila and rat primary neurons. Unexpectedly, a moderately high-amino acid diet also blocks dopamine neuron loss and motor deficits in Drosophila through a separate mechanism involving stress-responsive activation of 5'-AMP-activated protein kinase (AMPK) and neuroprotective induction of autophagy, implicating the importance of protein homeostasis to neuronal viability. At the highest amino acid diet of the range tested, PD-related neurodegeneration occurs in an age-related manner, but is also observed in control strains, suggesting that it is independent of mutant LRRK2 expression. We propose that dietary influences on protein synthesis and autophagy are critical determinants of LRRK2 neurodegeneration, opening up possibilities for future therapeutic intervention.SIGNIFICANCE STATEMENT Parkinson's disease (PD) prevalence is projected to rise as populations continue to age, yet there are no current therapeutic approaches that delay or stop disease progression. A broad role for leucine-rich repeat kinase 2 (LRRK2) mutations in familial and idiopathic PD has emerged. Here, we show that dietary amino acids are important determinants of neurodegeneration in a Drosophila model of LRRK2 PD. Restricting all amino acids effectively suppresses dopaminergic neuron loss and locomotor deficits and is associated with reduced protein synthesis, while moderately high amino acids similarly attenuate these PD-related phenotypes through a stress-responsive induction of 5'-AMP-activated protein kinase and autophagy. These studies suggest that diet plays an important role in the development of PD-related phenotypes linked to LRRK2.

Steffany Villalobos-Cantor

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