Inhibition of LRRK2 prevents endosomal trafficking deficits and lysosomal dysfunction

Identification: Rocha, Emily


Inhibition of LRRK2 prevents endosomal trafficking deficits and lysosomal dysfunction
E Rocha, R Di Maio, B De Miranda, M Keeny, S Castro, JT Greenamyre
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh PA
Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are a leading cause of familial Parkinson's disease (PD). LRRK2 is considered a multivalent kinase, however the precise mechanisms by which LRRK2 contributes to PD is not well understood. LRRK2 can localize to vesicular structures and is thought to play a role in endosomal trafficking and autophagy-lysosomal degradation through phosphorylation of various Ras Analog in Brain (Rab) GTPases. We aimed to determine whether LRRK2 kinase activity is implicated in the pathophysiology of the disease by disrupting endo-lysosomal trafficking and promoting endogenous accumulation of α-synuclein through excessive phosphorylation of specific Rab proteins.
Exposure to the mitochondrial complex I inhibitor, rotenone, causes neuropathological changes similar to idiopathic PD, including selective loss of dopamine (DA) neurons and accumulation of α-synuclein. In addition, rats treated with rotenone also display significant impairment in endo-lysosomal trafficking and increased endogenous LRRK2 kinase activity. The most striking observation is accumulation of Rab5 protein within the surviving DA neurons, a known LRRK2 kinase substrate and key regulator of endosomal trafficking. This observed accumulation of Rab5 may explain why rotenone impairs endo-lysosomal dysfunction and causes accumulation of α-synuclein. To determine whether LRRK2 initiates these pathogenic changes, we chose to pharmacologically block LRRK2 activity while concomitantly exposing rats to rotenone. Our dosing regimen successfully blocked LRRK2 activity in DA neurons, and prevented neurodegeneration and α-synuclein accumulation. In addition, blocking LRRK2 activity also prevented deficits in endo-lysosomal trafficking including restoring Rab5 levels in the dopaminergic neurons.  
These data suggest that increased LRRK2 kinase activity may prevent the maturation of late endosomes. This blockade early in the endosomal pathway may explain the downstream lysosomal and autophagy deficits. Therapeutics that target LRRK2, such as specific LRRK2 kinase inhibitors may have broad applicability and be useful for all PD-patients.
This work was supported by the Parkinson's foundation (ER) and NIH grants (JTG).


Credits: None available.

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