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. 2012 Dec;48(3):391-8.
doi: 10.1016/j.nbd.2012.06.018. Epub 2012 Jul 3.

Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS

Paloma González-Pérez  1 , Yubing Lu, Ru-Ju Chian, Peter C Sapp, Rudolph E Tanzi, Lars Bertram, Diane McKenna-Yasek, Fen-Biao Gao, Robert H Brown Jr
Affiliations

Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS

Paloma González-Pérez et al. Neurobiol Dis. 2012 Dec.

Abstract

Genetic variants in UBQLN1 gene have been linked to neurodegeneration and mutations in UBQLN2 have recently been identified as a rare cause of amyotrophic lateral sclerosis (ALS).

Objective: To test if genetic variants in UBQLN1 are involved in ALS.

Methods: 102 and 94 unrelated patients with familial and sporadic forms of ALS were screened for UBQLN1 gene mutations. Single nucleotide variants were further screened in a larger set of sporadic ALS (SALS) patients and unrelated control subjects using high-throughput Taqman genotyping; variants were further assessed for novelty using the 1000Genomes and NHLBI databases. In vitro studies tested the effect of UBQLN1 variants on the ubiquitin-proteasome system (UPS).

Results: Only two UBQLN1 coding variants were detected in the familial and sporadic ALS DNA set; one, the missense mutation p.E54D, was identified in a single patient with atypical motor neuron disease consistent with Brown-Vialetto-Van Laere syndrome (BVVLS), for whom c20orf54 mutations had been excluded. Functional studies revealed that UBQLN1E54D protein forms cytosolic aggregates that contain mislocalized TDP-43 and impairs degradation of ubiquitinated proteins through the proteasome.

Conclusions: Genetic variants in UBQLN1 are not commonly associated with ALS. A novel UBQLN1 mutation (E45D) detected in a patient with BVVLS altered nuclear TDP-43 localization in vitro, suggesting that UPS dysfunction may also underlie the pathogenesis of this condition.

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Figures

Fig.1
Fig.1. hUBQLN1E54D perturbs the distribution of TDP-43 protein in HEK293 cells
Co-expression of Flag-hUBQLN1E54D and TDP-43-EGFP redistributes TDP-43 to the cytoplasm of HEK293 cells, where TDP-43 co-localizes with mutant UBQLN1E54D, primarily in aggregate forms (i-l). This phenotype was not observed with UBQLN1WT (a-d) or UBQLN1S503C (e-h), although a loss of nuclear TDP-43 was observed in the latter case. Flag-hUBQLN1E54D and hUBQLN1E54D reproduced the results seen with UBQLN1E54D (m-t).
Fig. 2
Fig. 2. hUBQLN1E54D reduces the level of endogenous TDP-43 in both HEK293 cells and D. melanogaster
HEK293T cells were transfected with tagged (Fig 2A and B) and untagged (Fig 2C and D) human UBQLN1WT, UBQLN1S503C and UBQLNE54D constructs. Endogenous TDP-43 levels were significantly reduced in cells transfected with PrP-UBQLN1E54D and Flag-UBQLN1E54D when compared to hUBQLN1WT; transfection with hUBQLN1S503C did not produce this effect. The same effect was also evident after over-expression of UAS-HA-hUBQLN1WT, UAS-HA-hUBQLN1S503C and UAS-HA-hUBQLN1E54D in the eye of D. melanogaster (Fig.2 E and F).
Fig. 3
Fig. 3. UBQLN1 mutants did not influence FUS distribution in HEK293 cells
Nuclear distribution of FUS protein was not affected when co-expressing Flag-hUBQLN1E54D/S503C/WT and FUS-GFP.
Fig. 4
Fig. 4. Speculative model of the effect of UBQLN1E54D on TDP-43
The E54D mutation in UBQL-1 is presumed to prevent the UBL domain from interacting with the proteasome or autophagosomes. Consequently, polyubiquitinated proteins that bind UBQL1, like TDP-43, are not degraded and accumulate in cytoplasm.
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