INTRODUCTION: Glucocerebrosidase 1 mutations, the most common genetic contributor to Parkinson's disease (PD), have been associated with decreased glucocerebrosidase enzymatic activity in PD patients with glucocerebrosidase 1 mutations (glucocerebrosidase 1-PD). However, it is unknown whether this decrease in enzymatic activity leads to lysosphingolipid accumulations. METHODS: The levels of hexosylsphingosines, globotriaosylsphingosine, sphingomyelin, and sphingomyelin-509 were measured in dried blood spots from glucocerebrosidase 1-PD patients (n = 23), sporadic PD patients (n = 105), Gaucher disease patients (n = 32), and controls (n = 88) by liquid chromatography-tandem mass spectrometry. RESULTS: Glucocerebrosidase 1-PD patients had increased hexosylsphingosine levels when compared with sporadic PD patients (P < .001) and controls (P < .0001). Hexosylsphingosine levels were increased in glucocerebrosidase 1 mutation carriers of glucocerebrosidase 1 (L444P; N370S; n = 11, P = .001) and glucocerebrosidase 1 polymorphic variants (E326K, T369M) associated with PD (n = 12, P = .04) when compared with controls. CONCLUSIONS: Lysosphingolipid accumulations in PD patients who bear glucocerebrosidase 1 mutations suggest that substrate reduction therapy might be viewed as a possible strategy for glucocerebrosidase 1-PD treatment.
INTRODUCTION:Glucocerebrosidase 1 mutations, the most common genetic contributor to Parkinson's disease (PD), have been associated with decreased glucocerebrosidase enzymatic activity in PDpatients with glucocerebrosidase 1 mutations (glucocerebrosidase 1-PD). However, it is unknown whether this decrease in enzymatic activity leads to lysosphingolipid accumulations. METHODS: The levels of hexosylsphingosines, globotriaosylsphingosine, sphingomyelin, and sphingomyelin-509 were measured in dried blood spots from glucocerebrosidase 1-PDpatients (n = 23), sporadic PDpatients (n = 105), Gaucher diseasepatients (n = 32), and controls (n = 88) by liquid chromatography-tandem mass spectrometry. RESULTS:Glucocerebrosidase 1-PDpatients had increased hexosylsphingosine levels when compared with sporadic PDpatients (P < .001) and controls (P < .0001). Hexosylsphingosine levels were increased in glucocerebrosidase 1 mutation carriers of glucocerebrosidase 1 (L444P; N370S; n = 11, P = .001) and glucocerebrosidase 1 polymorphic variants (E326K, T369M) associated with PD (n = 12, P = .04) when compared with controls. CONCLUSIONS:Lysosphingolipid accumulations in PDpatients who bear glucocerebrosidase 1 mutations suggest that substrate reduction therapy might be viewed as a possible strategy for glucocerebrosidase 1-PD treatment.
Authors: Nurit Omer; Nir Giladi; Tanya Gurevich; Anat Bar-Shira; Mali Gana-Weisz; Tal Glinka; Orly Goldstein; Meir Kestenbaum; Jesse M Cedarbaum; Omar S Mabrouk; Kyle B Fraser; Julia C Shirvan; Avi Orr-Urtreger; Anat Mirelman; Avner Thaler Journal: Mov Disord Date: 2021-09-22 Impact factor: 9.698
Authors: T S Usenko; K A Senkevich; A I Bezrukova; G V Baydakova; K S Basharova; A S Zhuravlev; E V Gracheva; A V Kudrevatykh; I V Miliukhina; I V Krasakov; L A Khublarova; I V Fursova; D V Zakharov; A A Timofeeva; Y A Irishina; E I Palchikova; N M Zalutskaya; A K Emelyanov; E Y Zakharova; S N Pchelina Journal: Mol Neurobiol Date: 2022-01-23 Impact factor: 5.590
Authors: Victor Blokhin; Maria Shupik; Ulyana Gutner; Ekaterina Pavlova; Albert T Lebedev; Olga Maloshitskaya; Vsevolod Bogdanov; Sergey Sokolov; Alice Alessenko; Michael Ugrumov Journal: Biomolecules Date: 2022-01-06