Paul Roby

Introduction. Parkinson disease (PD) occurs in 1% of people over the age of 50 making it the second most common neurodegenerative disease^1,2. PD involves death of dopaminergic neurons in the substantia nigra pars compacta and alpha-synuclein deposition leading to Lewy body formation^1,2. Improvements in genetic testing have implicated many genetic factors with mutations of leucine-rich repeat kinase 2 (LRRK2) being the most frequent cause of familial PD³. Compared to idiopathic PD, LRRK2-PD has been shown to have an earlier onset⁴. LRRK2 is a gene involved in phosphorylation and regulation of autophagy that has multiple domains with the kinase domain appearing to be most important¹. Studies show the common LRRK2 mutation Gly2019Ser leads to increased LRRK2 kinase activity causing impairment of autophagy⁵. Other studies have indicated two main pathways influenced by LRRK2: mTOR/Unc-51-like kinase1 (ULK1) and Beclin-1/phosphatidylinositol 3-kinase (PI3K)³.  Understanding how LRRK2 mutations influence autophagy is important for developing potential pharmaceutical interventions for PD. Methods. H4 astroglioma cells were used to model cells damaged in PD⁵. Ser758 phosphorylation of ULK1 was analyzed as a function of dose and time⁵. LRRK2 kinase inhibitors such as LRRK2in1 were used⁵. Next, LRRK2 kinase inhibition and mTOR inhibition were added simultaneously to prove an mTORC1 independent phosphorylation of ULK1⁵. Questionnaires were provided to PD patients to compare motor and non-motor symptoms in LRRK2 risk variant patients versus non-carriers⁶. Results. Astroglioma cells with LRRK2in1 to inhibit LRRK2 kinase showed no change at 6/10 hours⁵. The 18-hour mark showed a significant dose-dependent increase in Ser758 ULK1 phosphorylation indicating increase in macroautophagy⁵. Combined mTORC1 inhibition with LRRK2 inhibition at the 18-hour mark showed Ser758 ULK1 remaining phosphorylated indicating phosphorylation occurred independently of the mTOR pathway⁵. In LRRK2 risk carriers, there was a significant increase in motor symptoms after 4 years when compared to non-carries through the Hoehn & Yahr scale⁶. Non-motor symptoms were also significantly reduced in non-carriers’ versus risk carriers at the 1-year mark in mood/apathy and wellbeing. However, these statistical differences did not hold for year 2-4⁶. Conclusions. Studies have found that short term LRRK2 kinase inhibition seems to promote autophagy independent of the mTOR/ULK1 pathway with long term LRRK2 kinase inhibition leading to reduced macroautophagy due to hyperphosphorylation at ULK1⁵. The change in autophagy over time could complicate potential pharmaceutical therapies utilizing LRRK2 inhibitors. Studies also indicate a different progression of PD for LRRK2 carriers relative to non-carriers suggesting need for individualized treatments⁶.

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