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Nuclear-import Receptors Can Dissolve Cytoplasmic Protein Aggregates Associated with Neurodegenerative Disorders Such as ALS

Key findings

  • Aggregates of nuclear proteins trapped in the cytoplasm are associated with degenerative disorders
  • Nuclear-import receptors (NIRs) bind to cytoplasmic proteins carrying nuclear-localization sequences (NLSs)
  • NIRs bind to NLSs in protein aggregates, dissolve the aggregates and restore nuclear localization
  • Pathological aggregates linked to neurodegenerative diseases are reversible

Several neurodegenerative disorders are characterized by abnormal protein aggregates in the cytoplasm. These aggregates are typically comprised of nuclear proteins known as RNA binding proteins (RBPs). Normally, nuclear import proteins (NIRs) recognize nuclear localization signals (NLSs) on RBPs and import them into the nucleus. However, several RBPs implicated in neurodegenerative disorders carry prion-like domains (PrLDs) which can cause them to become trapped in the cytoplasm as aggregates. Mutations in PrLDs appear to exacerbate the condition. Therefore, defects in nuclear transport have an important role in neurodegenerative disorders like amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and multisystem proteinopathy (MSP).

Massachusetts General Hospital postdoctoral researcher Fernande Freyermuth, PhD, is part of a multi-institutional consortium including the University of Pennsylvania and St. Jude Children's Research Hospital that recently conducted a study to assess how NIRs might be used to dissolve cytoplasmic aggregates. Their findings demonstrate that NIRs may serve as possible agents to dissolve cytoplasmic aggregates of RBPs, localize them to the nucleus and even prevent aggregate formation. The results of this study were published in the journal Cell.

NIRs bind to cytoplasmic proteins carrying NLSs. NIRs then associate with nucleoporins to facilitate movement of the NIR with its cargo across the nuclear membrane. Therefore, the team predicted that NIRs might also disrupt protein aggregates involved in neurodegenerative disorders. In vitro results from this study showed that intact NIR strongly inhibited the formation of aggregates. In vivo results showed that if the proteins in an aggregate carried an intact NLS, then NIR bound to the NLS, restored nuclear localization and function of the protein and rescued degeneration.

Neurodegeneration in ALS and FTD is thought to spread throughout the brain via cell-to-cell transmission of prion-like fibrils, which seed aggregate formation in each newly affected cell. The findings in this study indicate that NIR abolished aggregation even in preformed fibrils.

Each NIR extracts a single RBP monomer to form a soluble complex. The complex is then transported to the nucleus so that reaggregation in the cytoplasm cannot occur.

Under certain conditions, RBPs can transition from the liquid state to deleterious hydrogels. NIR was shown to directly bind to NLSs on proteins buried within a hydrogel and restore the proteins to the liquid state. When RBPs display disrupted NLS, NIRs can still weaken the hydrogels.

An MSP-linked mutation expressed in drosophila resulted in extensive mislocalization and aggregation of the mutant protein in the cytoplasm of muscle fibers. The researchers increased NIR expression in these cells, which reduced cytoplasmic aggregation, relocalized the protein into the nucleus and rescued the muscle degeneration.

Finally, the researchers restored the function of a protein mislocalized in cytoplasmic aggregates in cells from three patients with ALS. FUS protein normally resides in the nucleus where it regulates expression and splicing of several target genes. However, ALS mutations in the FUS gene led to mislocalization of FUS in the cytoplasm and the formation of abnormal protein inclusions. When NIR expression was increased in fibroblasts from these ALS patients, expression of the genes regulated by FUS was restored to normal levels.

In summary, this study showed that NLSs are disaggregation signals to NIRs. Therefore, NIRs have an essential role in heading off the devastating effects of aberrant protein aggregates in the cytoplasm. The findings in this study demonstrate that NIRs might be exploited to develop an effective therapy for ALS and other neurodegenerative disorders.

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