Rapamycin alleviates toxicity of different aggregate-prone proteins

Area of Science:

• Neurobiology
• Molecular Biology
• Pharmacology

Background:

• Neurodegenerative diseases often stem from intracellular protein aggregates, such as polyglutamine-expanded huntingtin (Huntington's disease) and mutant tau (tauopathies).
• Autophagy, a cellular degradation process, can clear these toxic protein inclusions.
• Rapamycin, a known autophagy inducer, previously demonstrated efficacy in clearing mutant huntingtin fragments and reducing toxicity.

Purpose of the Study:

• To investigate the broader therapeutic potential of rapamycin beyond Huntington's disease.
• To determine if rapamycin can enhance the clearance of various aggregate-prone proteins and mitigate their associated toxicity.
• To assess rapamycin's efficacy in models of tauopathies.

Main Methods:

• Treatment with rapamycin in cellular and animal models.
• Assays to measure the clearance of polyglutamine-expanded proteins and polyalanine-expanded proteins.
• Assessment of protein aggregation, specifically insoluble tau.
• Evaluation of toxicity in relevant disease models.

Main Results:

• Rapamycin significantly enhanced the autophagic clearance of diverse polyglutamine-expanded proteins and a polyalanine-expanded protein.
• This enhanced clearance correlated with reduced protein toxicity.
• Rapamycin treatment decreased toxicity in Drosophila models expressing wild-type or mutant tau.
• Observed reductions in insoluble tau levels in tauopathy models were linked to rapamycin's therapeutic effects.

Conclusions:

• Rapamycin demonstrates a broad applicability for enhancing the clearance of various toxic protein aggregates.
• The findings suggest rapamycin holds significant therapeutic promise for a wider range of aggregate-related neurodegenerative diseases, including tauopathies.
• Autophagy induction via rapamycin represents a viable strategy for treating protein aggregation disorders.