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@ARTICLE{Zanella:280250,
      author       = {Zanella, Pietro and Loss, Isabel and Parlato, Rosanna and
                      Weishaupt, Jochen H and Sala, Carlo and Verpelli, Chiara and
                      Boeckers, Tobias M and Catanese, Alberto},
      title        = {{ALS} {M}utations {S}hift the {I}soelectric {P}oint of the
                      {KIF}5{A} {C} {T}erminal {I}nducing {P}rotein {A}ggregation
                      and {TDP}-43 {M}islocalization.},
      journal      = {The journal of neuroscience},
      volume       = {45},
      number       = {31},
      issn         = {0270-6474},
      address      = {Washington, DC},
      publisher    = {Soc.},
      reportid     = {DZNE-2025-00928},
      pages        = {e1658242025},
      year         = {2025},
      abstract     = {Amyotrophic lateral sclerosis (ALS) is a devastating
                      neurodegenerative disease characterized by death of lower
                      and upper motor neurons. Although the mechanism behind the
                      selective neuron loss is still unclear, several
                      heterogeneous genes have been causally linked to ALS. KIF5A
                      encodes for a neuronally enriched kinesin involved in
                      protein transport, and mutations within this gene have been
                      causally linked to different motor neuron diseases. The
                      mutations identified in ALS patients are mostly predicted to
                      alter its mRNA splicing, leading to a frameshift mutation
                      and an aberrant 39-aa-long sequence in the C-terminal domain
                      of KIF5A. Here we found that ALS-related KIF5A mutations
                      induce the accumulation of the mutant form of the protein in
                      human motoneurons, which are also characterized by the
                      cytosolic mislocalization of TDP-43. This ALS hallmark was
                      even exacerbated upon overexpression of the ALS-KIF5A
                      protein in cells differentiated from healthy controls and
                      primary neurons, suggesting a pathological connection
                      between the cellular load of the mutant protein and TDP-43
                      pathology. While the terminal domain of the WT isoform is
                      characterized by an acid isoelectric point (pI), the ALS
                      variant presents a basic pI due to the altered aminoacidic
                      composition of this sequence. We thus generated a KIF5A-ALS
                      isoform that retained part of the aberrant sequence but with
                      lower pI. The overexpression of this mutated variant led to
                      significantly lower protein aggregation and TDP-43
                      mislocalization than the ALS mutant. Our data show that
                      re-establishing the correct pI rescues KIFA aggregation and
                      significantly reduces the cytoplasmic mislocalization of
                      TDP-43.},
      keywords     = {Kinesins: genetics / Kinesins: metabolism / Kinesins:
                      chemistry / Humans / Amyotrophic Lateral Sclerosis: genetics
                      / Amyotrophic Lateral Sclerosis: metabolism / Amyotrophic
                      Lateral Sclerosis: pathology / DNA-Binding Proteins:
                      metabolism / DNA-Binding Proteins: genetics / Mutation:
                      genetics / Motor Neurons: metabolism / Animals / Protein
                      Aggregation, Pathological: genetics / Protein Aggregation,
                      Pathological: metabolism / Cells, Cultured / ALS (Other) /
                      KIF5A (Other) / TDP-43 (Other) / aggregation (Other) /
                      isoelectric point (Other) / Kinesins (NLM Chemicals) / KIF5A
                      protein, human (NLM Chemicals) / DNA-Binding Proteins (NLM
                      Chemicals) / TARDBP protein, human (NLM Chemicals)},
      cin          = {AG Böckers},
      ddc          = {610},
      cid          = {I:(DE-2719)1910002},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40555518},
      pmc          = {pmc:PMC12311770},
      doi          = {10.1523/JNEUROSCI.1658-24.2025},
      url          = {https://pub.dzne.de/record/280250},
}