Polyglutamine disorders: Pathogenesis and potential drug interventions

• Published in: Life sciences (1973) Vol. 344; p. 122562
• Main Authors: Tandon, Shweta, Aggarwal, Prerna, Sarkar, Surajit
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-05-2024
• Subjects: Animal-models; Cell Death - genetics; Humans; Inclusion bodies; Neurodegeneration; Neurotoxicity Syndromes - metabolism; Peptides; Poly(Q) disorders; Therapeutics; Neurodegeneration; Animal-models; Inclusion bodies; Poly(Q) disorders; Therapeutics
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2024.122562

Polyglutamine/poly(Q) diseases are a group nine hereditary neurodegenerative disorders caused due to abnormally expanded stretches of CAG trinucleotide in functionally distinct genes. All human poly(Q) diseases are characterized by the formation of microscopically discernable poly(Q) positive aggregates, the inclusion bodies. These toxic inclusion bodies are responsible for the impairment of several cellular pathways such as autophagy, transcription, cell death, etc., that culminate in disease manifestation. Although, these diseases remain largely without treatment, extensive research has generated mounting evidences that various events of poly(Q) pathogenesis can be developed as potential drug targets. The present review article briefly discusses the key events of disease pathogenesis, model system-based investigations that support the development of effective therapeutic interventions against pathogenesis of human poly(Q) disorders, and a comprehensive list of pharmacological and bioactive compounds that have been experimentally shown to alleviate poly(Q)-mediated neurotoxicity. Interestingly, due to the common cause of pathogenesis, all poly(Q) diseases share etiology, thus, findings from one disease can be potentially extrapolated to other poly(Q) diseases as well.
[Display omitted]
•Polyglutamine/poly(Q) disorders are single gene driven autosomal dominant neurodegenerative diseases.•Abnormal expansion of CAG repeats in the mutated gene codes for a pathogenic protein with an expanded poly(Q) stretch.•Proteins with elongated poly(Q) repeats form neurotoxic aggregates and triggers a cascade of pathogenic events.•Impaired proteostasis, mitochondrial function and cellular transcription are key pathogenic events of poly(Q) disorders.•Such pathogenic events have emerged as potential drug target(s) for further development of novel therapeutics.