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Increased Ubqln2 expression causes neuron death in transgenic rats.

Bo Huang1, Qinxue Wu1, Hongxia Zhou2

  • 1Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Journal of Neurochemistry
|July 27, 2016
PubMed
Summary

Excess ubiquilin 2 (UBQLN2) protein, even in its normal form, can be toxic to neurons. This study in rats suggests that an overabundance of UBQLN2, not just mutations, contributes to neurodegenerative diseases like ALS and FTLD.

Keywords:
ALSFTLDRpt1Ubqln2p62rats

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Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Pathogenic mutations in ubiquilin 2 (UBQLN2) are linked to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).
  • Previous research in animal models indicated that these diseases arise from a toxic gain of function, rather than a loss of function, associated with UBQLN2 mutations.
  • The precise mechanism by which UBQLN2 mutations induce neurodegeneration remains unclear.

Purpose of the Study:

  • To investigate whether an enhanced function of wild-type UBQLN2 contributes to the pathogenesis observed in UBQLN2-related neurodegenerative diseases.
  • To develop a more relevant animal model for studying UBQLN2-associated neurodegeneration.

Main Methods:

  • Created transgenic rats over-expressing wild-type human UBQLN2.
  • Generated transgenic rats over-expressing wild-type rat Ubqln2 to account for potential species-specific interactions.
  • Assessed neuronal function, spatial learning, and the formation of protein inclusions in the created transgenic rat models.

Main Results:

  • Over-expression of both human and rat wild-type Ubqln2 in transgenic rats led to neuronal death and spatial learning deficits.
  • The observed pathologies were similar to those seen in transgenic rats with pathogenic UBQLN2 mutations.
  • Excess wild-type UBQLN2 formed protein aggregates that attracted key cellular components involved in protein degradation pathways (sequestosome-1 and 26S proteasome).

Conclusions:

  • The findings suggest that an overabundance of UBQLN2, irrespective of mutation, is detrimental to neuronal health.
  • Enhanced or uncontrolled UBQLN2 function, not solely its mutation, plays a significant role in the pathogenesis of UBQLN2-related neurodegenerative diseases.
  • These results highlight the potential toxicity of elevated UBQLN2 levels and implicate functional enhancement in disease mechanisms.