Thomas Patterson

Introduction Parkinson’s disease is noted as a loss of dopaminergic neurons in the substantia nigra. Parkinson’s disease is considered the second most common neurodegenerative disease and affects 2% of all people above 65 years old. While there has been a vast number of risk factors, I wanted to focus on leucine rich repeat kinase 2 (LRRK2) gene mutations as an important factor in the development of the disease. LRRK2 autophosphorylation via heterologous kinases and phosphatases in the N-terminus. Interestingly, neurodegeneration has been closely linked to a specific G2019S mutation in the LRRK2 gene which leads to altered GTPase activity and kinase activity.⁵ This leads to an overactive kinase that causes a dysregulation in the neuroinflammatory response through release of cytokines activating microglia.⁵ This overactive activation of macrophage and microglia has been theorized to leads to destruction of the dopaminergic neurons in the substantia nigra.⁴ To summarize, since the overactive kinase appears to be the problem, I wanted to take a deeper look to the effects that occurred downstream after the serine and Rab sites are activated. Methods There were antibodies specific for the LRRK2 gene and the phosphorylated Ser935 that were used in a western blot after incubation. To measure kinase activity, a LanthaScreen kinase assay and a AlphaScreen assay were used. Mass spectrometry was also used along with western blots and antibodies. A protein capillary electrophoresis was also used to measure the phosphorylated LRRK2 concentrations. Results It was observed in a recent study in 2020 that the G2019S mice were seen to exhibit an age-dependent decline in Ser935 phosphorylated levels correlating with the age dependent decline of parkinsons.² The results reflected that the dysregulation of Rab35 phosphorylation caused degeneration of dopaminergic neurons in vivo after neurite shortening was seen in the substantia nigra and pars compacta locations.² A recent study showed that increased LRRK2 kinase activity causes neurotoxicity. ⁸ Another recent study showed that the peripheral immune activation was specifically correlated with LRRK2 gene mutations that increase LRRK2 kinase activity.¹ Conclusion Low levels of Ser935 phosphorylation in LRRK2 R1441C cause RAB10 phosphorylation even though phosphorylated Ser935 is normally required for RAB29 recruitment of LRRK2. LRRK2 pathogenic mutations that alter autologous and heterologous LRRK2 phosphorylation can be used as predictive biomarkers and can potentially be used for better personalized treatment. The importance of this study is that it identified axonal damage as another marker for disease. The paper also suggested that kinase inhibition and inhibiting GTP binding can be used to treat G2019S variants.

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