Ubqln2, a member of the ubiquilin family, is a proteasomal shuttle factor in the ubiquitin-proteasome system (UPS) [2,4]. It actively participates in the degradation of misfolded and redundant proteins via UPS and macroautophagy, playing a crucial role in proteostasis regulation [2,4]. Ubqln2 also has emerging functions such as acting as a chaperone in protein folding and protecting proteins before membrane insertion [4]. Animal models, especially gene-knockout (KO) or conditional-knockout (CKO) mouse models, are valuable for studying its functions [2,4].

Mutations in Ubqln2 can cause amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) [1,2,4]. In Parkin-mediated mitophagy, after Parkin-dependent ubiquitination of damaged mitochondria, Ubqln2 is recruited to poly-ubiquitinated mitochondria through the UBA domain. It cooperates with HSP70 to promote UPS-driven degradation of outer mitochondrial membrane proteins, triggering autophagosomal recognition of the inner mitochondrial membrane receptor PHB2. ALS/FTD pathogenic mutations in Ubqln2 impair mitophagy in primary cultured neurons, linking dysfunctional mitophagy to Ubqln2-mediated neurodegeneration [1]. In addition, Ubqln2 regulates the domesticated gag-pol retrotransposon 'paternally expressed gene 10 (PEG10)' in human cells and tissues. In ALS patient spinal cord tissue, PEG10 gag-pol is elevated, implicating PEG10's retrotransposon-like activity as a contributing mechanism in ALS [3].

In summary, Ubqln2 is essential for proteostasis, with key functions in protein degradation and mitophagy. The study of KO/CKO mouse models has revealed its significant role in neurodegenerative diseases like ALS and FTD, helping to understand the molecular mechanisms underlying these diseases and potentially providing new directions for treatment strategies [1,2,3,4].

References:

1. Ma, Qilian, Xin, Jiaqi, Peng, Qiang, Wang, Hongfeng, Ying, Zheng. 2023. UBQLN2 and HSP70 participate in Parkin-mediated mitophagy by facilitating outer mitochondrial membrane rupture. In EMBO reports, 24, e55859. doi:10.15252/embr.202255859. https://pubmed.ncbi.nlm.nih.gov/37501540/

2. Renaud, Laurence, Picher-Martel, Vincent, Codron, Philippe, Julien, Jean-Pierre. 2019. Key role of UBQLN2 in pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia. In Acta neuropathologica communications, 7, 103. doi:10.1186/s40478-019-0758-7. https://pubmed.ncbi.nlm.nih.gov/31319884/

3. Black, Holly H, Hanson, Jessica L, Roberts, Julia E, Lau, Cristina I, Whiteley, Alexandra M. 2023. UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS. In eLife, 12, . doi:10.7554/eLife.79452. https://pubmed.ncbi.nlm.nih.gov/36951542/

4. Lin, Brian C, Higgins, Nicole R, Phung, Trong H, Monteiro, Mervyn J. 2021. UBQLN proteins in health and disease with a focus on UBQLN2 in ALS/FTD. In The FEBS journal, 289, 6132-6153. doi:10.1111/febs.16129. https://pubmed.ncbi.nlm.nih.gov/34273246/