Nanobodies as allosteric modulators of Parkinson’s disease-associated LRRK2

Mutations in the gene coding for Leucine-Rich Repeat Kinase 2 (LRRK2) are a leading cause of the inherited form of Parkinson’s disease (PD), while LRRK2 overactivation is also associated with the more common idiopathic form of PD. LRRK2 is a large multi-domain protein, including a GTPase as well as a Ser/Thr protein kinase domain. Common disease-causing mutations increase LRRK2 kinase activity, presenting LRRK2 as an attractive target for inhibitory drug design. Currently, drug development has mainly focused on ATP-competitive kinase inhibitors. Here, we report the identification and characterization of a variety of Nanobodies that bind to different LRRK2 domains and inhibit or activate LRRK2 activity in cells and in vitro. Importantly, diverse groups of Nanobodies were identified that inhibit LRRK2 kinase activity through a mechanism that does not involve binding to the ATP pocket or even to the kinase domain. Moreover, while certain Nanobodies completely inhibit the LRRK2 kinase activity, we also identified Nanobodies that specifically inhibit the phosphorylation of Rab protein substrates. Finally, in contrast to current type-I kinase inhibitors, the studied kinase-inhibitory Nanobodies did not induce LRRK2 microtubule association. These comprehensively characterized Nanobodies represent versatile tools to study the LRRK2 function and mechanism, and can pave the way toward novel diagnostic and therapeutic strategies for PD

Nanobodies as allosteric modulators of Parkinson's disease-associated LRRK2

Mutations in the gene coding for leucine-rich repeat kinase 2 (LRRK2) are a leading cause of the inherited form of Parkinson’s disease (PD), while LRRK2 overactivation is also associated with the more common idiopathic form of PD. LRRK2 is a large multidomain protein, including a GTPase as well as a Ser/Thr protein kinase domain. Common, disease-causing mutations increase LRRK2 kinase activity, presenting LRRK2 as an attractive target for drug discovery. Currently, drug development has mainly focused on ATP-competitive kinase inhibitors. Here, we report the identification and characterization of a variety of nanobodies that bind to different LRRK2 domains and inhibit or activate LRRK2 in cells and in in vitro. Importantly, nanobodies were identified that inhibit LRRK2 kinase activity while binding to a site that is topographically distinct from the active site and thus act through an allosteric inhibitory mechanism that does not involve binding to the ATP pocket or even to the kinase domain. Moreover, while certain nanobodies completely inhibit the LRRK2 kinase activity, we also identified nanobodies that specifically inhibit the phosphorylation of Rab protein substrates. Finally, in contrast to current type I kinase inhibitors, the studied kinase-inhibitory nanobodies did not induce LRRK2 microtubule association. These comprehensively characterized nanobodies represent versatile tools to study the LRRK2 function and mechanism and can pave the way toward novel diagnostic and therapeutic strategies for PD

Une thérapie des rôles figés : l'apport de G. Kelly

Van Rillaer J. Une thérapie des rôles figés : l'apport de G. Kelly. In: Bulletin de psychologie, tome 23 n°285, 1970. Le psychodrame. pp. 793-798

Interest of psychological interventions in dialysis: Exploratory Study

Patients suffering from end stage renal disease (ESRD) have a very reduced quality of life accompanied by a severe emotional distress (high worries-anxiety-depression). However, in Belgium, no regular psychological intervention is proposed to dialyzed patients. Our objective is to show that psychological intervention can significantly decrease the emotional distress of patients with ESRD. Eleven sessions of structured interventions are proposed to ESRD patients. Eligibility criteria are to be major, to not present confusion or/and dementia, to have been on dialysis treatment for at least 3 months, to have obtained 14 or more on HAD-scale. Interventions carry on the management of anxious and depressive symptoms and of the disease itself. This constitutes three independent modules. Questionnaires are filled in by the patients at various stages to evaluate the anxiety and the depression (HADS), the worries (Penn State) and the quality of life (KDQoL-SF). Results for the 47 ESRD patients show a significant reduction of the scores of anxiety, depression and worries and a significant growth of quality of life. In parallel a decrease in the serum calcium-phosphorus product analyzed before dialysis has been noted