Current Molecular Medicine

David W. Li  
College of Medicine
University of Nebraska Medical Center
Omaha, NE


Converging Pathways in the Occurrence of Endoplasmic Reticulum (ER) Stress in Huntingtons Disease

Author(s): R. Vidal, B. Caballero, A. Couve and C. Hetz

Affiliation: Institute of Biomedical Sciences, University of Chile. Independencia 1027, Santiago, P.O. BOX 70086, Chile.

Keywords: Huntington's disease, ER stress, protein misfolding, Unfolded protein response, Huntingtin, endoplasmic reticulum, neurodegenerative disease, cognitive defects, dementia, polyglutamine, spinobulbar muscular atrophy, spinocerebellar ataxias, Machado-Joseph Disease, mutations, protein conformational disorders, aggregation, apoptosis, translocation, homeostasis, PERK signaling, morphogenesis, phenotype, mutant Htt, tunicamycin, vesicular trafficking, autophagy, ERAD, calnexin cycle, chaperones, familial amyotrophic lateral sclerosis, brefeldin A, ER/Golgi trafficking, Parkinson's disease, Synuclein, NMDAR, AMPA receptors, axonal transport, Macroautophagy, autophagosome, Beclin-1, lymphoblasts, poly(Q), hapsigargin, SERCA inhibitor


A variety of neurological diseases including Huntingtons disease (HD), Alzheimers disease and Parkinsons disease share common neuropathology, primarily featuring the presence of abnormal protein inclusions containing specific misfolded proteins. Mutations leading to expansion of a poly-glutamine track in Huntingtin cause HD, and trigger its misfolding and aggregation. Recent evidence indicates that alterations in the secretory pathway, in particular the endoplasmic reticulum (ER), are emerging features of HD. Although it is not clear how cytoplasmic/nuclear located mutant Huntingtin alters the function of the ER, several reports indicate that mutant Huntingtin affects many essential processes related to the secretory pathway, including inhibition of ER-associated degradation, altered ER/Golgi vesicular trafficking and axonal transport, disrupted autophagy and abnormal ER calcium homeostasis. All these alterations are predicted to have a common pathological outcome associated to disturbance of protein folding and maturation pathways at the ER, generating chronic ER stress and neuronal dysfunction. Here, we review recent evidence involving ER stress in HD pathogenesis and discuss possible therapeutic strategies to target organelle function in the context of disease.

Order Reprints Order Eprints Rights & PermissionsPrintExport

Article Details

Page: [1 - 12]
Pages: 12
DOI: 10.2174/156652411794474419