tailieunhanh - Báo cáo khoa hoc : TDP-43: the relationship between protein aggregation and neurodegeneration in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Accumulations of aggregated proteins are a key feature of the pathology of all of the major neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) was brought into this fold quite recently with the discovery of TDP-43 (TAR DNA binding protein, 43 kDa) inclusions in nearly all ALS cases. | IFEBS Journal MINIREVIEW TDP-43 the relationship between protein aggregation and neurodegeneration in amyotrophic lateral sclerosis and frontotemporal lobar degeneration Robert H. Baloh Neuromuscular Division Department of Neurology Hope Center for NeurologicalDisorders Washington University Saint Louis MO USA Keywords amyotrophic lateral sclerosis frontotemporal dementia motor neuron disease prion domain protein aggregation RNA metabolism Correspondence R. H. Baloh Department of Neurology 660 South Euclid Avenue Box 8111 Saint Louis MO 63110 USA Fax 314 362 3752 Tel 314 362 6981 E-mail rbaloh@ Received 10 February 2011 revised 6 April 2011 accepted 11 April 2011 doi Accumulations of aggregated proteins are a key feature of the pathology of all of the major neurodegenerative diseases. Amyotrophic lateral sclerosis ALS was brought into this fold quite recently with the discovery of TDP-43 TAR DNA binding protein 43 kDa inclusions in nearly all ALS cases. In part this discovery was fueled by the recognition of the clinical overlap between ALS and frontotemporal lobar degeneration where ubiquitinated TDP-43 inclusions were first identified. Later the identification of TDP-43 mutations in rare familial forms of ALS confirmed that altered TDP-43 function can be a primary cause of the disease. However the simple concept that TDP-43 is an aggregation-prone protein that forms toxic inclusions capable of promoting neurodegeneration has not been upheld by initial investigations. This review discusses observations from human pathology cell culture and animal model systems to highlight our somewhat murky understanding of the relationship between TDP-43 aggregation and neurodegeneration. Introduction Aside from neuronal cell loss and reactive gliosis aberrant protein aggregation is the key feature of the pathology of most neurodegenerative diseases including Alzheimer s disease Parkinson s disease Huntington s disease and many others 1