Huntington's Disease

Neurobiology of Disease
Volume 27, Issue 1, July 2007, Pages 108-116

SummaryPlusdoi:10.1016/j.nbd.2007.04.012

Severe deficiency of the fatty acid amide hydrolase (FAAH) activity segregates with the Huntington's disease mutation in peripheral lymphocytes

Natalia Battista^a^,^b^,¹, Monica Bari^b^,^c^,¹, Alessia Tarditi^d^,², Caterina Mariotti^e^,², Anne-Catherine Bachoud-Lévi^f^,², Chiara Zuccato^d, Alessandro Finazzi-Agrò^c, Silvia Genitrini^e, Marc Peschanski^g, Stefano Di Donato^e^,³, Elena Cattaneo^d^,³ and Mauro Maccarrone^a^,^b^,^,³^,
^aDepartment of Biomedical Sciences, University of Teramo, Piazza A. Moro 45, I-64100 Teramo, Italy
^bEuropean Center for Brain Research (CERC)/IRCCS S. Lucia Foundation, 00179 Rome, Italy
^cDepartment of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata”, 00133 Rome, Italy
^dDepartment of Pharmacological Sciences and UniStem – Centre for Stem Cell Research, University of Milan, 20133 Milan, Italy
^eDivision of Biochemistry and Genetics, Carlo Besta Neurological Institute, 20133 Milan, Italy
^fINSERM U841, team 1 “Neuropsychologie Interventionnelle”, 94010 Créteil, France
^gINSERM/UEVE UMR861, I-STEM Genopole Campus 1, 91030 Evry Cedex, France
Received 20 February 2007; revised 25 April 2007; accepted 27 April 2007. Available online 8 May 2007.

Abstract

The search for peripheral markers of neurodegenerative diseases aims at identifying molecules that could help in monitoring the effects of future therapeutics in easily accessible cells. Here we focused on the involvement of the endocannabinoid system in Huntington's disease (HD). We assayed peripheral lymphocytes from HD patients and healthy controls, and found that the activity of the fatty acid amide hydrolase (FAAH), the enzyme that degrades the endocannabinoid anandamide (AEA), was dramatically decreased (down to less than 10%) in HD compared to healthy subjects. Concomitantly, the endogenous levels of AEA were 223c 6-fold higher in HD versus healthy lymphocytes, while the other elements of the endocannabinoid system were not affected by HD. Low FAAH activity in HD lymphocytes was not due to down-regulation of protein expression, but rather to blockage of enzyme activity by a cytosolic and irreversible inhibitor. Finally, pre-HD patients showed defective FAAH activity, as did the brain of HD patients compared with healthy controls. Taken together, our data indicate that FAAH activity in lymphocytes mirrors some of the metabolic changes which take place in the brain, it is a measurable non-genetic peripheral marker that segregates with the HD mutation, and it might serve as a target to test chemicals active on the widespread toxic effects of the mutant protein.

Keywords: Endocannabinoid; Enzyme inhibition; FAAH; Huntington's disease; Lymphocyte

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doi:10.1016/j.neuint.2007.06.031

Symptom-related changes of endocannabinoid and palmitoylethanolamide levels in brain areas of R6/2 mice, a transgenic model of Huntington's disease

Tiziana Bisogno^a, Alberto Martire^b, Stefania Petrosino^a^,^c, Patrizia Popoli^b^,^, and Vincenzo Di Marzo^a^,^,
^aEndocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli (Naples), Italy
^bDepartment of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
^cDipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Fisciano, Italy
Received 29 May 2007; revised 18 June 2007; accepted 28 June 2007. Available online 4 July 2007.

Abstract

Previous studies have shown an impairment of the endocannabinoid system in experimental models of Huntington's disease. In transgenic R6/2 mice, created by inserting exon 1 of the human IT15 mutant gene into the mouse, and exhibiting 150 CAG repeats as well as signs of HD, a progressive decline of CB₁ receptor expression and an abnormal sensitivity to CB₁ receptor stimulation have been reported. Here, by using isotope-dilution liquid chromatography–mass spectrometry, we investigated whether the levels of three endogenous neuroprotective substances, the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and palmitoylethanolamide (PEA), are altered in different brain areas of transgenic R6/2 versus wild-type (WT) mice at two different disease phases, i.e. in pre-symptomatic (4.5 weeks) or overtly symptomatic (10 weeks) R6/2 mice versus age-matched WT mice (n = 4/group). Except for a 223c 25% decrease in 2-AG levels in the cortex, no significant changes in endocannabinoid and PEA levels were observed in pre-symptomatic R6/2 versus WT mice. By contrast, in symptomatic R6/2 mice the levels of all three compounds were significantly ( 223c 30–60%) decreased in the striatum, whereas little changes were observed in the hippocampus, and a 223c 28% decrease of 2-AG levels, accompanied by a 223c 50% increase of AEA levels, was found in the cortex. These findings show that endocannabinoid levels change in a disease phase- and region-specific way in the brain of R6/2 mice and indicate that an impaired endocannabinoid system is a hallmark of symptomatic HD, thus suggesting that drugs inhibiting endocannabinoid degradation might be used to treat this disease.

Keywords: Cannabinoid; Anandamide; 2-Arachidonoylglycerol; CB1 receptor; Basal ganglia; Locomotion; Cortex

Corresponding authors. Tel.: +39 081 8675093; fax: +39 081 8041770.

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