Multifaceted interactions mediated by intrinsically disordered regions play key roles in alpha synuclein aggregation.

The aggregation of Alpha Synuclein (α-Syn) into fibrils is associated with the pathology of several neurodegenerative diseases. Pathologic aggregates of α-Syn adopt multiple fibril topologies and are known to be transferred between cells via templated seeding. Monomeric α-Syn is an intrinsically disordered protein (IDP) with amphiphilic N-terminal, hydrophobic-central, and negatively charged C-terminal domains. Here, we review recent work elucidating the mechanism of α-Syn aggregation and identify the key and multifaceted roles played by the N- and C-terminal domains in the initiation and growth of aggregates as well as in the templated seeding involved in cell-to-cell propagation. The charge content of the C-terminal domain, which is sensitive to environmental conditions like organelle pH, is a key regulator of intermolecular interactions involved in fibril growth and templated propagation. An appreciation of the complex and multifaceted roles played by the intrinsically disordered terminal domains suggests novel opportunities for the development of potent inhibitors against synucleinopathies.

Assessing fidelity in individual and family therapy for adolescent substance abuse.

This study introduces an observational measure of fidelity in evidence-based practices for adolescent substance abuse treatment. The Therapist Behavior Rating Scale-Competence (TBRS-C) measures adherence and competence in individual cognitive-behavioral therapy and multidimensional family therapy for adolescent substance abuse. The TBRS-C assesses fidelity to the core therapeutic goals of each approach and also contains global ratings of therapist competence. Study participants were 136 clinically referred adolescents and their families observed in 437 treatment sessions. The TBRS-C demonstrated strong interrater reliability for goal-specific ratings of treatment adherence, and modest reliability for goal-specific and global ratings of therapist competence, evidence of construct validity, and discriminant validity with an observational measure of therapeutic alliance. The utility of the TBRS-C for evaluating treatment fidelity in field settings is discussed.