Heart disease remains the most common cause of death and disability in our society. However, the face of this disease has evolved considerably in the decades since cardiovascular scientists began to understand the cellular and molecular mechanisms of its pathophysiology. Today, nearly 90% of patients hospitalized for a heart attack not only survive but also return to their normal activities and work within weeks, if not sooner — a vast improvement in outcome as compared with decades earlier. However, the evolution in the treatment of acute cardiovascular disease has also been paralleled by an increase in the number of patients with chronic debilitation due to heart failure. Despite advances in our understanding of the neurohormonal basis of heart failure, current therapies for heart failure are limited, and the need for additional therapies remains great. Protein homeostasis plays a role in the development of numerous disorders. Misfolded proteins are central in the pathophysiology of neurodegenerative diseases such as Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. In the past several years, misfolded proteins have been found to play a role in the pathophysiology of common human cardiac diseases such as pathologic cardiac hypertrophy and dilated and ischemic cardiomyopathies, leading to the suggestion that protein misfolding is a key contributor to the progression of heart failure. In this review, we explore the contribution of protein misfolding to the pathophysiology of cardiac disease, describing why these proteins become misfolded and how the innate systems that usually dispose of them break down. We then discuss how the knowledge obtained from studying protein misfolding in other diseases, such as Alzheimer’s disease, may aid us in understanding the pathophysiological mechanisms of cardiac diseases and developing new treatments that focus on preventing or reversing protein misfolding in the heart.
Monte S. Willis & Cam Patterson
New England Journal of Medicine, Jan 31, 2013
Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of Aβ accumulation in late-onset AD.
Dimitrije Krstic & Irene Knuesel
Nature Reviews Neurology 9, 25-34 January 2013
The formation, maintenance and reorganization of synapses are critical for brain development and the responses of neuronal circuits to environmental challenges. Here we describe a novel role for peroxisome proliferator-activated receptor γ co-activator 1α, a master regulator of mitochondrial biogenesis, in the formation and maintenance of dendritic spines in hippocampal neurons. In cultured hippocampal neurons, proliferator-activated receptor γ co-activator 1α overexpression increases dendritic spines and enhances the molecular differentiation of synapses, whereas knockdown of proliferator-activated receptor γ co-activator 1α inhibits spinogenesis and synaptogenesis. Proliferator-activated receptor γ co-activator 1α knockdown also reduces the density of dendritic spines in hippocampal dentate granule neurons in vivo. We further show that brain-derived neurotrophic factor stimulates proliferator-activated receptor γ co-activator-1α-dependent mitochondrial biogenesis by activating extracellular signal-regulated kinases and cyclic AMP response element-binding protein. Proliferator-activated receptor γ co-activator-1α knockdown inhibits brain-derived neurotrophic factor-induced dendritic spine formation without affecting expression and activation of the brain-derived neurotrophic factor receptor tyrosine receptor kinase B. Our findings suggest that proliferator-activated receptor γ co-activator-1α and mitochondrial biogenesis have important roles in the formation and maintenance of hippocampal dendritic spines and synapses.
Cheng A, Wan R, Yang JL, Kamimura N, Son TG, Ouyang X, Luo Y, Okun E, Mattson MP
Nature Reviews Neurology 9, 25-34 January 2013