UBQLN2/P62 cellular recycling pathways in amyotrophic lateral sclerosis and frontotemporal dementia

• Published in: Muscle & nerve 2012-02, Vol.45 (2), p.157-162
• Main Authors: Fecto, Faisal, Siddique, Teepu
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; autophagy; autophagy, protein degradation; Biological and medical sciences; Brain - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Frontotemporal Dementia - pathology; frontotemporal lobe dementia; Humans; Medical sciences; Neurology; p62; protein degradation; Sequestosome-1 Protein; SQSTM1; ubiquilin 2; ubiquitin-proteasome system; Ubiquitins - genetics; Ubiquitins - metabolism; UBQLN2
• ISSN: 0148-639X; 1097-4598
• DOI: 10.1002/mus.23278

Recent findings highlight a pathologic and functional convergence in amyotrophic lateral sclerosis (ALS) and amyotrophic lateral sclerosis with frontotemporal dementia (ALS‐FTD) at the level of protein recycling and disposal. Genes linked to rare cases of familial ALS and ALS‐FTD, like UBQLN2, OPTN, SQSTM1/p62, and VCP, may converge onto a unifying pathogenic pathway and thereby provide novel therapeutic targets common to a spectrum of etiologically diverse forms of ALS and ALS‐FTD. Interactions between these genes need to be further explored to understand their common molecular pathways. Future efforts should be directed toward generation and characterization of in vivo models to dissect the pathogenic mechanisms of ALS and ALS‐FTD and the role of protein degradation pathways, both centrally, at the cell body, and peripherally, at the level of the synapse. Such efforts will rapidly accelerate the discovery of new drugs that regulate accumulation of pathogenic proteins and their downstream consequences in ALS and ALS‐FTD and, possibly, other neurodegenerative diseases as well. Muscle Nerve, 2012