Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1(H46R)-expressing ALS mouse model

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective loss of upper and lower motor neurons. Recent studies have shown that mutations in SQSTM1 are linked to ALS. SQSTM1 encodes SQSTM1/p62 that regulates not only autophagy via the association with MAP1LC3/LC3 and ubiquitinated proteins but also the KEAP1-NFE2L2/Nrf2 anti-oxidative stress pathway by interacting with KEAP1. Previously, we have demonstrated that loss of SQSTM1 exacerbates disease phenotypes in a SOD1(H46R)-expressing ALS mouse model. To clarify the effects of SQSTM1 overexpression in this model, we generated SQSTM1 and SOD1(H46R) double-transgenic (SQSTM1;SOD1(H46R)) mice. SQSTM1;SOD1(H46R) mice exhibited earlier disease onset and shorter lifespan than did SOD1(H46R) mice. Conversely, disease progression after the onset rather slightly but significantly slowed in SQSTM1;SOD1(H46R) mice. However, there were observable differences neither in the number of Nissl positive neurons nor in the distribution of ubiquitin-positive and/or SQSTM1-positive aggregates between SOD1(H46R) and SQSTM1;SOD1(H46R) mice. It was noted that these protein aggregates were mainly observed in neuropil, and partly localized to astrocytes and/or microglia, but not to MAP2-positive neuronal cell bodies and dendrites at the end-stage of disease. Nonetheless, the biochemically-detectable insoluble SQSTM1 and poly-ubiquitinated proteins were significantly and progressively increased in the spinal cord of SQSTM1;SOD1(H46R) mice compared to SOD1(H46R) mice. These results suggest that overexpression of SQSTM1 in SOD1(H46R) mice accelerates disease onset by compromising the protein degradation pathways. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13041-018-0373-8) contains supplementary material, which is available to authorized users.