TY  - EJOU
AU  - Basharova, Katerina 
AU  - Bezrukova, Anastasia 
AU  - Kopytova, Alena 
AU  - Lavrinova, Anna 
AU  - Baydakova, Galina 
AU  - Miliukhina, Irina 
AU  - Zakharova, Ekaterina 
AU  - Emelyanov, Anton 
AU  - Pchelina, Sofya 
AU  - Usenko, Tatiana 

TI  - LRRK2 Inhibition Differently Affects Lysosomal Hydrolase Activity and Autophagy-Related Protein Levels in PBMC-Derived Macrophages from Patients with Different Synucleinopathies
T2  - BIOCELL

PY  - 
VL  - 
IS  - 
SN  - 1667-5746

AB  - <b>Objectives:</b> Synucleinopathies—Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)—involve alpha-synuclein aggregation and lysosomal dysfunction. We conducted a longitudinal study of lysosomal hydrolase activities and lysosphingolipid levels in blood and PBMC-derived macrophages from patients, and assessed the effects of LRRK2 inhibition (MLi-2). <b>Methods:</b> Blood and PBMC-derived macrophages were collected from patients with idiopathic PD (iPD), DLB, MSA, and controls. Enzyme activities (GCase, ASMase, GLA, GALC) and lysosphingolipids (HexSph, LysoGb3, LysoSM) were measured. Autophagy markers (p62, LC3B-II) and cathepsin D (CTSD) were analyzed by western blot. Effects of MLi-2 were evaluated in macrophages. <b>Results:</b> All synucleinopathy groups showed reduced blood GCase activity and elevated HexSph levels, with the highest HexSph levels observed in MSA (<i>p</i> &lt; 0.05). DLB exhibited reduced ASMase, whereas MSA showed broader sphingolipid disruption (reduced ASMase activity, increased GLA and GALC activities, elevated LysoGb3 levels (<i>p</i> &lt; 0.05)). In iPD, LysoGb3 levels increased, and LysoSM levels decreased. In PBMC-derived macrophages, MSA showed reduced GCase, GALC, and ASMase activities. HexSph levels were elevated in all groups, while LysoGb3 levels were increased in iPD and MSA (<i>p</i> &lt; 0.05). DLB macrophages showed increased mature CTSD, whereas MSA cells exhibited reduced CTSD and p62 (<i>p</i> &lt; 0.05). MLi-2 had minimal effects on enzyme activities and lipid levels. It increased p62 in iPD, reduced CTSD in DLB (<i>p</i> &lt; 0.05), and had no effect in MSA (<i>p</i> &gt; 0.05). <b>Conclusion:</b> HexSph may represent a common marker of synucleinopathies, while MSA demonstrates the most pronounced lysosomal dysfunction. Limited effects of LRRK2 inhibition suggest a minor role for this pathway in sporadic synucleinopathies.
KW  - Synucleinopathies; lysosomal hydrolases; leucine-rich repeat kinase 2; MLi-2; autophagy

DO  - 10.32604/biocell.2026.079585