LRRK2 kinaz aktivitesinin engellenmesi, kolinerjik nöronlarda presenilin 1 Ile416Thr mutasyonu ile ilişkili patolojiye karşı korur.

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Familial Alzheimer’s disease (FAD) is an accelerated form of dementia that affects cholinergic neurons. Unfortunately, despite several efforts, no single drug or treatment has shown complete efficacy. Therefore, it is imperative to find effective therapeutic agents. Previously, it has been shown that the PSEN1 I416T variant induces FAD-like neuropathology in cholinergic-like neurons (ChLNs), which is characterized by intracellular accumulation of the A(beta) peptide, oxidation of the stress sensor protein DJ-1, abnormal phosphorylation of the TAU protein at residue S202/T205, loss of mitochondrial membrane potential (deltapsi(m)), and activation of the pro-apoptotic proteins TP53, c-JUN, PUMA, and cleaved caspase 3 (CC3). We report for the first time that PSEN1 I416T induces (i) abnormal phosphorylation of LRRK2 kinase at residue S935, concomitant with (ii) phosphorylated alpha-synuclein (aSyn) at residue S129 and abnormal accumulation of autophagosomes and atypical increase (alkaline) in vesicular lysosomal pH, thereby provoking a profound alteration in autophagy in ChLNs. Here, we also demonstrate for the first time that the potent LRRK2 inhibitor PF-06447475 (hereafter referred to as PF475) almost completely attenuated PSEN1 I416T-induced proteinopathy, oxidative stress (OS), and apoptosis and restored autophagy to an activity comparable to untreated wild-type (WT) ChLNs. Overall, PF475 restored the survival of mutant ChLNs. Since LRRK2 kinase inhibitors are promising therapeutic drugs for the treatment of Parkinson’s disease (PD), our findings suggest that LRRK2 may also be a potential target for therapeutic intervention in FAD.

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