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

Recent findings highlight a pathologic and functionalconvergence in amyotrophic lateral sclerosis (ALS) andamyotrophic lateral sclerosis with frontotemporal dementia(ALS-FTD) at the level of protein recycling and disposal. Geneslinked to rare cases of familial ALS and ALS-FTD, likeUBQLN2, OPTN, SQSTM1/p62, and VCP, may converge onto aunifying pathogenic pathway and thereby provide novel therapeutictargets common to a spectrum of etiologically diverseforms of ALS and ALS-FTD. Interactions between these genesneed to be further explored to understand their common molecularpathways. Future efforts should be directed toward generationand characterization of in vivo models to dissect thepathogenic mechanisms of ALS and ALS-FTD and the role ofprotein degradation pathways, both centrally, at the cell body,and peripherally, at the level of the synapse. Such efforts willrapidly accelerate the discovery of new drugs that regulateaccumulation of pathogenic proteins and their downstream consequences in ALS and ALS-FTD and, possibly, other neurodegenerativediseases as well.