piperidines and Machado-Joseph-Disease

No disease-modifying treatment exists for the fatal neurodegenerative polyglutamine disease known both as Machado-Joseph disease and spinocerebellar ataxia type 3. As a potential route to therapy, we identified small molecules that reduce levels of the mutant disease protein, ATXN3. Screens of a small molecule collection, including 1250 Food and Drug Administration-approved drugs, in a novel cell-based assay, followed by secondary screens in brain slice cultures from transgenic mice expressing the human disease gene, identified the atypical antipsychotic aripiprazole as one of the hits. Aripiprazole increased longevity in a Drosophila model of Machado-Joseph disease and effectively reduced aggregated ATXN3 species in flies and in brains of transgenic mice treated for 10 days. The aripiprazole-mediated decrease in ATXN3 abundance may reflect a complex response culminating in the modulation of specific components of cellular protein homeostasis. Aripiprazole represents a potentially promising therapeutic drug for Machado-Joseph disease and possibly other neurological proteinopathies.

Topics: Animals; Animals, Genetically Modified; Antipsychotic Agents; Aripiprazole; Ataxin-3; Brain; Disease Models, Animal; Drosophila; Drug Evaluation, Preclinical; Gene Expression Regulation; HEK293 Cells; Humans; Machado-Joseph Disease; Mice; Mutant Proteins; Nerve Tissue Proteins; Organ Culture Techniques; Peptides; Piperidines; Pyrans; Pyrazoles

To elucidate characteristic changes of brain acetylcholinesterase (AChE) in cerebellar degenerative disorders. Eight patients with the cerebellar variant of multiple system atrophy (MSA-C), 7 patients with spinocerebellar ataxia type-3 (SCA-3), 3 patients with SCA-6, and 13 healthy age-matched volunteers participated in this study. Brain AChE activity was measured by [(11)C] N-methylpiperidin-4-yl propionate PET in all subjects. Brain AChE activities were significantly decreased in the thalamus (-27%) and the posterior lobe of cerebellar cortex (-36%) in patients with MSA-C and in the thalamus (-23%) in patients with SCA-3 compared with healthy controls (P < 0.01). Thalamic AChE activities of SCA-3 patients were negatively correlated with the unified Parkinson's disease rating scale motor subscore (P < 0.001). AChE activities were not significantly altered in the cerebral cortex in any disease group. Reduction of AChE activities in the thalamus and cerebellum in MSA and in the thalamus in SCA-3 suggest that cholinergic modulating drugs may have a role in the treatment of ataxia and other symptoms in these disorders.

Topics: Acetylcholinesterase; Adult; Aged; Brain; Carbon Radioisotopes; Cerebellar Cortex; Cerebral Cortex; Female; Humans; Image Processing, Computer-Assisted; Machado-Joseph Disease; Magnetic Resonance Imaging; Male; Middle Aged; Multiple System Atrophy; Neurologic Examination; Piperidines; Positron-Emission Tomography; Propionates; Spinocerebellar Ataxias; Spinocerebellar Degenerations; Thalamus