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• Ataxin-2 needs to be considered in TDP-43 positive patients with PSP-like parkinsonism and motor neuron disease
  Christos Proukakis
  Published on: 15 June 2011

• Published on: 15 June 2011

  Ataxin-2 needs to be considered in TDP-43 positive patients with PSP-like parkinsonism and motor neuron disease

  • Christos Proukakis, Senior Lecturer

  Sir

  Espay and colleagues report a detailed clinical and pathological study of two unrelated individuals with rapidly progressive atypical parkinsonism (similar to progressive supranuclear palsy, PSP), and additional frontotemporal and motor neuron involvement, in whom TDP-43 inclusion pathology was demonstrated. (1) Sequencing of PGRN and TARDBP gene coding regions was negative, and therefore no genetic cause...

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  Sir

  Espay and colleagues report a detailed clinical and pathological study of two unrelated individuals with rapidly progressive atypical parkinsonism (similar to progressive supranuclear palsy, PSP), and additional frontotemporal and motor neuron involvement, in whom TDP-43 inclusion pathology was demonstrated. (1) Sequencing of PGRN and TARDBP gene coding regions was negative, and therefore no genetic cause was identified. An additional gene that needs to be considered, however, in light of important very recent evidence, is ATXN2, in which pure CAG expansions (range 34-59 repeats) lead to spinocerebellar ataxia (SCA2).

  The encoded protein ataxin-2 was shown to interact with TDP-43, which plays a key role in motor neuron disease (MND), and modulate its toxicity, with intermediate CAG expansions in ATXN2 (27-33 repeats) appearing to be risk factors for MND. (2) This has already been confirmed in other studies, 3-4 and importantly a clear association with PSP was also shown, (3) with the risk highest for both MND and PSP for repeats >30. Rather than the pure CAG repeats which occur in the typical SCA2 phenotype, CAA interruptions of the CAG expansion repeats are found in motor neuron disease and PSP. (3-4)

  It is therefore plausible that the unexplained PSP / MND overlap phenotype with TDP-43 inclusions may have been associated with interrupted intermediate size expansions in ATXN2, and confirmation of this would advance understanding of the pathology of this novel type of neurodegeneration. Testing of DNA from different tissues and brain regions available would also allow the investigation of possible mosaicism, which has been previously reported in SCA2 (5) and could help explain the phenotypic variation of this type of ATXN2 mutation.

  1. Espay AJ, Spina S, Houghton DJ, Murrell JR, de Courten-Myers GM, Ghetti B, et al. Rapidly progressive atypical parkinsonism associated with frontotemporal lobar degeneration and motor neuron disease. J Neurol Neurosurg Psychiatry 2011;82:751-3.

  2. Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 2010;466:1069-75.

  3. Ross OA, Rutherford NJ, Baker M, Soto-Ortolaza AI, Carrasquillo MM, Dejesus-Hernandez M, et al. Ataxin-2 repeat-length variation and neurodegeneration. Hum Mol Genet 2011. doi:10.1093/hmg/ddr227

  4. Yu Z, Zhu Y, Chen-Plotkin AS, Clay-Falcone D, McCluskey L, Elman L, et al. PolyQ repeat expansions in ATXN2 associated with ALS are CAA interrupted repeats. PLoS One 2011;6:e17951.

  5. Matsuura T, Sasaki H, Yabe I, Hamada K, Hamada T, Shitara M, et al. Mosaicism of unstable CAG repeats in the brain of spinocerebellar ataxia type 2. J Neurol 1999;246:835-9.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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