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Unveiling the degradative route of the V247M α-sarcoglycan mutant responsible for LGMD-2D.

Significance Statement

Type-2D limb girdle muscular dystrophy (LGMD) is a severe, although rare, disorder affecting skeletal muscle. It is due to mutations of the gene coding for α-sarcoglycan that, together with Beta-, Gamma- and Delta-sarcoglycan, forms a key complex of the skeletal muscle membrane. Most of the mutations identified so far, are missense mutations causing the incorrect folding of the protein, that is recognized by the Endoplasmic Reticulum quality control and eventually degraded by the ubiquitin-proteasome system. The reduction or absence of the mutated α-sarcoglycan leads to a parallel decrease of the wild type partners and to the development of the disease. In many cases the protein, even though mutated, retains its function. For this reason we hypothesized that actions to avoid mutant degradation could be beneficial to counteract the dystrophic phenotype in patients. This can be achieved not only by inhibiting components of the degradative pathway, as described in this work, but also by helping the folding of the mutated α-sarcoglycan, via small molecules acting as pharmacological chaperones (Sandonà et al. patent pending, P127272.WO.01).

Unveiling the degradative route of the V247M α-sarcoglycan mutant responsible for LGMD-2D

Journal Reference

Bianchini E, Fanin M, Mamchaoui K, Betto R, Sandonà D.

Hum Mol Genet. 2014 Mar 9.

Department of Biomedical Sciences, and
Department of Neurosciences, University of Padova, Padova 35131, Italy
Institut de Myologie, UPMC UM76, INSERM U974, CNRS UMR 7215, Paris 6, France
Institute of Neuroscience, Consiglio Nazionale delle Ricerche, Padova 35131, Italy
*To whom correspondence should be addressed at: Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, 35131 Padova, Italy.



Many membrane and secretory proteins that fail to pass quality control in the endoplasmic reticulum (ER) are dislocated into the cytosol and degraded by the proteasome. In applying rigid rules, however, quality control sometimes discharges proteins that, even though defective, retain their function. The unnecessary removal of such proteins represents the pathogenetic hallmark of diverse genetic diseases, in the case of {DELTA}F508 mutant of cystic fibrosis transmembrane conductance regulator being probably the best known example. Recently, the inappropriate proteasomal degradation of skeletal muscle sarcoglycans ({Alpha}, {Beta}, {Gamma} and {Delta}) with missense mutation has been proposed to be at the bases of mild-to-severe forms of limb girdle muscular dystrophy (LGMD) known as type 2D, 2E, 2C and 2F, respectively. The quality control pathway responsible for sarcoglycan mutantdisposal, however, is so far unexplored. Here we reveal key components of the degradative route of V247M {Alpha}-sarcoglycan mutant, the second most frequently reported mutation in LGMD-2D. The disclosure of the pathway, which is led by the E3 ligases HRD1 and RFP2, permits to identify new potential druggable targets of a disease for which no effective therapy is at present available. Notably, we show that the pharmacological inhibition of HRD1 activity rescues the expression of V247-α-sarcoglycan both in a heterologous cell model and in myotubes derived from a LGMD-2D patient carrying the L31P/V247M mutations. This represents the first evidence that the activity of E3 ligases, the enzymes in charge of mutant fate, can be eligible for drug interventions to treat sarcoglycanopathy.

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