Mutations in the UBQLN2 gene, which encodes a ubiquitin-like protein called ubiquilin2, cause dominant X-linked juvenile and adult-onset amyotrophic lateral sclerosis (ALS) and ALS/dementia. The study identified five mutations in UBQLN2, all involving proline residues in a PXX repeat region, which are associated with ALS and ALS/dementia. These mutations impair protein degradation, leading to abnormal protein aggregation and neurodegeneration. The study also found that ubiquilin2 is involved in the formation of skein-like inclusions in ALS and ALS/dementia, and that these inclusions are also present in the brains of patients with ALS/dementia. The study further showed that ubiquilin2 is a common component in the skein-like inclusions of various types of ALS, including sporadic and familial forms. The study also found that ubiquilin2 pathology is present in the hippocampus of patients with ALS/dementia, and that this pathology is associated with dementia. The study also showed that ubiquilin2 mutations impair the ubiquitin-mediated proteasomal degradation pathway, which is critical for the pathogenesis of ALS and ALS/dementia. The findings suggest that ubiquilin2 is involved in the pathogenesis of ALS and ALS/dementia, and that targeting ubiquilin2 may be a potential therapeutic approach for these diseases.Mutations in the UBQLN2 gene, which encodes a ubiquitin-like protein called ubiquilin2, cause dominant X-linked juvenile and adult-onset amyotrophic lateral sclerosis (ALS) and ALS/dementia. The study identified five mutations in UBQLN2, all involving proline residues in a PXX repeat region, which are associated with ALS and ALS/dementia. These mutations impair protein degradation, leading to abnormal protein aggregation and neurodegeneration. The study also found that ubiquilin2 is involved in the formation of skein-like inclusions in ALS and ALS/dementia, and that these inclusions are also present in the brains of patients with ALS/dementia. The study further showed that ubiquilin2 is a common component in the skein-like inclusions of various types of ALS, including sporadic and familial forms. The study also found that ubiquilin2 pathology is present in the hippocampus of patients with ALS/dementia, and that this pathology is associated with dementia. The study also showed that ubiquilin2 mutations impair the ubiquitin-mediated proteasomal degradation pathway, which is critical for the pathogenesis of ALS and ALS/dementia. The findings suggest that ubiquilin2 is involved in the pathogenesis of ALS and ALS/dementia, and that targeting ubiquilin2 may be a potential therapeutic approach for these diseases.