A LRRK2/dLRRK-mediated lysosomal pathway that contributes to glial cell death and DA neuron survival

Mutations in leucine-rich repeat kinase 2 ( LRRK2 ) are the most common cause of familial and sporadic Parkinson’s disease (PD). A plethora of evidence has indicated a role for LRRK2 in endolysosomal trafficking in neurons, while LRRK2 function in glia, although highly expressed, remains largely unknown. Here we present evidence that LRRK2/dLRRK mediates a glial lysosomal pathway that contributes to the mechanism of PD. Independent of its kinase activity, glial LRRK2/dLRRK knockdown in the immortalized microglial cells or flies results in enlarged and swelling lysosomes fewer in number. These lysosomes are less mobile, wrongly acidified, and exhibit defective membrane permeability and reduced activity of the lysosome hydrolase cathespin B. In addition, microglial LRRK2 depletion causes increased Caspase 3 levels, leading to glial apoptosis, dopaminergic neurodegeneration, and locomotor deficits in an age-dependent manner. Taken together, these findings demonstrate a functional role of LRRK2/dLRRK in regulating the glial lysosomal pathway; deficits in lysosomal biogenesis and function linking to glial apoptosis potentially underlie the mechanism of DA neurodegeneration, contributing to the progression of PD.