This report describes amyotrophic lateral sclerosis 15 (ALS15), which is a subtype of amyotrophic lateral sclerosis; ALS15 exhibits sex-linked dominant inheritance. An alternative title for ALS15 is 'amyotrophic lateral sclerosis 15, with or without frontotemporal dementia'. The human gene implicated in this disease is UBQLN2, which encodes one of a family of ubiquitin-like proteins that play a role in the regulation of different protein degradation pathways and are thought to functionally link the ubiquitination machinery to the proteasome. There is a single orthologous gene in Drosophila, Dmel\Ubqn, for which RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated. Dmel\Ubqn is also orthologous to other ubiquilins in human, including UBQLN1 and UBQLN4.
Multiple UAS constructs of the human Hsap\UBQLN2 gene have been introduced into flies, including wild-type and variants associated with ALS15. Variant(s) implicated in human disease tested (as transgenic human gene, UBQLN2): the P497H and P525S variant forms of the human gene have been introduced into flies. An Hsap\UBQLN2 transgene carrying 4 variants (P497H, P506T, P509S, and P525S) has also been characterized in flies. Pan-neuronal expression of either wild-type or disease-associated variants results climbing defects; the phenotype is more severe for the disease-associated variants. High levels of pan-neuronal expression results in lethality.
Ubiquitous reduction in Dmel\Ubqn expression effected by RNAi results in lethality. Neuronal reduction effected by RNAi results in locomotor and neuroanatomy defects; accumulation of polyubiquitinated proteins is observed. Physical and genetic interactions of Dmel\Ubqn have been described; see below and in the Ubqn gene report.
[updated Jun. 2018 by FlyBase; FBrf0222196]
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996, pubmed:8875253). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. [from MIM:105400, 2015.02.11]
[AMYOTROPHIC LATERAL SCLEROSIS 15 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; ALS15](https://omim.org/entry/300857)
[UBIQUILIN 2; UBQLN2](https://omim.org/entry/300264)
Amyotrophic lateral sclerosis-15 with or without frontotemporal dementia (ALS15) is caused by mutation in the UBQLN2 gene; it exhibits X-linked dominant inheritance. [from MIM:300857; 2018.06.28]
UBQLN2 encodes an ubiquitin-like protein that plays a role in the regulation of different protein degradation mechanisms and pathways including ubiquitin-proteasome system (UPS), autophagy and the endoplasmic reticulum-associated protein degradation (ERAD) pathway. Ubiquilins physically associate with both proteasomes and ubiquitin ligases, thus, are thought to functionally link the ubiquitination machinery to the proteasome. [Gene Cards, UBQLN2; 2018.06.29]
The UBQLN2 gene encodes ubiquilin-2, a member of the ubiquilin family of proteins that regulate the degradation of ubiquitinated proteins by the proteasome. [from MIM:300264; 2018.06.28]
High-scoring ortholog of human UBQLN1, UBQLN2, UBQLN4; moderate-scoring ortholog of UBQLNL and UBQLN3 (2 Drosophila to 5 human). Dmel\Ubqn shares 46-50% identity and 63-67% similarity with UBQLN1, UBQLN2, UBQLN4; it shares 26-32% identity and 44-46% similarity with UBQLNL and UBQLN3.
