Loss of function of the RNA-binding protein TDP-43 is seen in neurodegenerative diseases, such as ALS, Huntington’s disease and Alzheimer’s disease. A study led by Ludwig San Diego’s Don Cleveland reported online in Science in December that RNA-binding deficient TDP-43—which is produced by neurodegeneration-causing mutations or biochemical modifications to the protein—drives TDP-43 de-mixing into liquid spherical shells with liquid cores in the nuclei of neurons. Don and his colleagues named these structures anisosomes and identified the major components of the liquid core to be HSP70 family chaperones, whose activity, powered by the molecule ATP, maintains the liquidity of shells and cores. In animal studies, inhibiting the
proteasome—which degrades proteins—within neurons to mimic the aging-related decline in its activity induced the formation of TDP-43-containing spherical shells. The shells convert into aggregates when ATP levels drop. These findings suggest the TDP-43 aggregation seen in neurodegenerative diseases may have its origins in anisosomes. The study also explains the peripheral neuropathy caused by bortezomib, a proteasome inhibitor used to treat multiple myeloma. The researchers showed that anisosomes form in sensory neurons in bortezomib-treated mice and rats and are thus likely to form in multiple myeloma patients who develop peripheral neuropathy.
This article appeared in the April 2021 issue of Ludwig Link. Click here to download a PDF (1.4 MB).