rifampin and Protein-Aggregation--Pathological

A host of human diseases, including Parkinson's disease and Dementia with Lewy bodies, are suspected to be directly linked to protein aggregation. Amyloid protein aggregates and oligomeric intermediates of α-synuclein are observed in synucleinopathies and considered to be mediators of cellular toxicity. Hence, α-synuclein has seen as one of the leading and most compelling targets and is receiving a great deal of attention from researchers. Nevertheless, there is no neuroprotective approach directed toward Parkinson's disease or other synucleinopathies so far. In this review, we summarize the available data concerning inhibitors of α-synuclein aggregation and their advancing towards clinical use. The compounds are grouped according to their chemical structures, providing respective insights into their mechanism of action, pharmacology, and pharmacokinetics. Overall, shared structure-activity elements are emerging, as well as specific binding modes related to the ability of the modulators to establish hydrophobic and hydrogen bonds interactions with the protein. Some molecules with encouraging in vivo data support the possibility of translation to the clinic.

Topics: alpha-Synuclein; Amyloidogenic Proteins; Drug Discovery; Humans; Protein Aggregation, Pathological; Structure-Activity Relationship

Mutant huntingtin (mHtt) aggregation in the nucleus is the most readily apparent phenotype and cause of neuronal death in Huntington's disease (HD). Inhibiting mHtt aggregation reduces cell death in the brain and is thus a promising therapeutic approach. The results of the present study demonstrated that mHtt aggregation in the nucleus was altered by the activity of multidrug resistance protein 1 (MDR1), which was experimentally modulated by verapamil, siRNA and an expression vector. MDR1 detoxifies drugs and metabolites through its excretory functions in the membrane compartment, thereby protecting cells against death or senescence. When they were treated with verapamil, R6/2 mice showed a progressive decline in rotarod performance and increased mHtt aggregation in the brain. Using neuronal stem cells from R6/2 mice, we developed an in vitro HD model to test mHtt accumulation in the nuclei of neurons. When MDR1 activity in cells was decreased by verapamil or siRNA, mHtt aggregation in the nuclei increased, whereas the induction of MDR1 resulted in a decrease in mHtt aggregation. Thus, our data provide evidence that MDR1 plays an important role in the clearance of mHtt aggregation and may thus be a potential target for improving the survival of neurons in Huntington's disease.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Cells, Cultured; Disease Models, Animal; Female; Humans; Huntingtin Protein; Huntington Disease; Immunohistochemistry; Male; Mice, Transgenic; Motor Activity; Mutation; Nerve Tissue Proteins; Neurons; Nucleic Acid Synthesis Inhibitors; Protein Aggregation, Pathological; Reverse Transcriptase Polymerase Chain Reaction; Rifampin; RNA Interference; Vasodilator Agents; Verapamil