Long-term inhibition of mutant LRRK2 hyper-kinase activity reduced mouse brain α-synuclein oligomers without adverse effects

Abstract

Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration in nigrostriatal and cortical brain regions associated with pathogenic α-synuclein (αSyn) aggregate/oligomer accumulation. LRRK2 hyperactivity is a disease-modifying therapeutic target in PD. However, LRRK2 inhibition may be associated with peripheral effects, albeit with unclear clinical consequences. Here, we significantly reduced αSyn oligomer accumulation in mouse striatum through long-term LRRK2 inhibition using GNE-7915 (specific brain-penetrant LRRK2 inhibitor) without causing adverse peripheral effects. GNE-7915 concentrations in wild-type (WT) mouse sera and brain samples reached a peak at 1 h, which gradually decreased over 24 h following a single subcutaneous (100 mg/kg) injection. The same dose in young WT and LRRK2R1441G mutant mice significantly inhibited LRRK2 kinase activity (Thr73-Rab10 and Ser106-Rab12 phosphorylation) in the lung, which dissipated by 72 h post-injection. 14-month-old mutant mice injected with GNE-7915 twice weekly for 18 weeks (equivalent to ~13 human years) exhibited reduced striatal αSyn oligomer and cortical pSer129-αSyn levels, correlating with inhibition of LRRK2 hyperactivity in brain and lung to WT levels. No GNE-7915-treated mice showed increased mortality or morbidity. Unlike reports of abnormalities in lung and kidney at acute high doses of LRRK2 inhibitors, our GNE-7915-treated mice did not exhibit swollen lamellar bodies in type II pneumocytes or abnormal vacuolation in the kidney. Functional and histopathological assessments of lung, kidney and liver, including whole-body plethysmography, urinary albumin-creatinine ratio (ACR), serum alanine aminotransferase (ALT) and serum interleukin-6 (inflammatory marker) did not reveal abnormalities after long-term GNE-7915 treatment. Long-term inhibition of mutant LRRK2 hyper-kinase activity to physiological levels presents an efficacious and safe disease-modifying therapy to ameliorate synucleinopathy in PD.

Regulatory imbalance between LRRK2 kinase, PPM1H phosphatase, and ARF6 GTPase disrupts the axonal transport of autophagosomes

“…The degradation of other cargos may also be affected, including the synaptically-enriched protein alpha-synuclein, a key protein in PD pathology and an established substrate of autophagy (Farfel-Becker et al, 2019;Friedman et al, 2012;Vogiatzi et al, 2008). Consistent with this possibility, exacerbated alpha-synuclein aggregation has been linked to expression of hyperactive LRRK2 (Bieri et al, 2019;Ho et al, 2022;MacIsaac et al, 2020;Schapansky et al, 2018;Volpicelli-Daley et al, 2016). Ongoing work to examine the degradation of alphasynuclein in cellular and animal models of PD should shed further light on this question.…”

Regulatory imbalance between LRRK2 kinase, PPM1H phosphatase, and ARF6 GTPase disrupts the axonal transport of autophagosomes

“… 43 – 45 Consistent with this possibility, exacerbated alpha-synuclein aggregation has been linked to expression of hyperactive LRRK2. 24 , 46 – 49 Ongoing work to examine the degradation of alpha-synuclein in cellular and animal models of PD should shed further light on this question. Of additional interest, we observe low levels of AV pausing in WT conditions, consistent with baseline WT levels of LRRK2 activity.…”

Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

“…The discovery of importance of the gut-brain axis in PD development opens a new approach for the search of therapeutic targets and biomarkers detection [ 95 , 96 ]. However, there are definite gaps in our knowledge and new research is needed for a better understanding of the role and interrelationships of α-synuclein with the vagus nerve, with the enteric nervous system, altered intestinal permeability, and inflammation [ 96 , 97 ].…”

“…One of the promising agents causing the reduction of α-synuclein oligomer accumulation is GNE-7915, specific inhibitor of the long-term brain-penetrant leucine-rich repeat kinase 2 (LRRK2 or PARK8). This inhibitor significantly decreases oligomers in the striatum without causing adverse peripheral effects [ 97 ]. Inhibition of mutant LRRK2 hyper-kinase activity to normal physiological levels offers an encouraging and safe disease-modifying therapy to improve the course of synucleinopathies.…”