TDP-43, Protein Aggregation, and Amyotrophic Lateral Sclerosis
TDP-43, Protein Aggregation, and Amyotrophic Lateral Sclerosis
US Neurology, 2010;5(2):35-8
Abstract
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder and the third most common neurodegenerative cause of adult death after Alzheimer’s and Parkinson’s diseases. TAR DNA binding protein (TDP-43) has been found to be a major component of inclusion bodies in motor neurons of ALS patients. Inclusion bodies are protein aggregates considered a pathological hallmark of neurodegeneration. Our group and eight independent research groups screened TDP-43 for mutations. Overall, 19 missense mutations and one truncating mutation were identified only in ALS patients. These mutations were not found in a considerable number of controls sequenced in several independent studies. Ten of these mutations were found in patients with a family history of ALS. To further support a pathogenic role, the mutations segregated with the disease in three families, including one family with a significant logarithm of odds (LOD) score. Nineteen of these 20 mutations are located in the C-terminus of the TDP-43 protein. These mutations could disrupt several of the already known functions of TDP-43, including nuclear localization, exon splicing, and RNA and heterogenous ribonucleoprotein particle (hnRNP) binding, or could introduce a novel gain of function that is toxic to motor neurons. In the future, animal and cellular models using these mutations should elucidate the role of TDP-43 mutations in ALS pathogenesis and could provide new means to test pharmaceutical compounds for this neurological disease.
Keywords
Amyotrophic lateral sclerosis, TARDBP, TDP-43, motor neuron disease, neurodegenerative disorder, human genetics
Disclosure: The authors have no conflicts of interest to declare.
Received: January 5, 2009 Accepted: June 8, 2009
Correspondence: Guy A Rouleau, MD, PhD, JA de Sève Pavilion, Room Y-3633, 1560, Sherbrooke St East, Montreal, QC H2L 4M1, Canada. E: guy.rouleau@umontreal.ca
Clinical Features of Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, is a neurological disorder characterized by the selective loss of upper and lower motor neurons in the brain and spinal cord. ALS is characterized by progressive muscle weakness, atrophy, and spasticity. The typical age at onset for most ALS patients is between 45 and 60 years, with an average survival of less than three years. The final fatal event is often the loss of the motor neurons that innervate the respiratory muscles and diaphragm. The worldwide incidence of ALS is one to two new cases per 100,000/year, whereas its prevalence is four to six affected individuals per 100,000, with a lifetime risk of ALS of one in 1,000. Most cases—approximately 90%—of ALS are sporadic (SALS), thus lacking an overt genetic cause. The remaining 10% of cases are mostly inherited in a dominant manner and are thus referred to as familial ALS (FALS). Sporadic and familial patients are largely clinically indistinguishable.1 ALS is traditionally viewed as lacking in cognitive impairment; however, a diagnosis of frontotemporal dementia (FTD), a neurological disorder characterized by neurodegeneration of the frontal lobe of the brain, has been reported in 3–15% of ALS cases.2 The human impact of ALS is enormous as it significantly affects a patient’s quality of life, with patients losing their ability to eat, speak, and live independently. At present, while significant advances have been made in palliative therapies, there is no cure or means to significantly slow disease progression. Indeed, currently just one Canadian Agency for Drugs and Technologies in Health (CADTH)/US Food and Drug Administration (FDA)-approved therapy exists (Riluzole), and it offers only a modest slowing of disease progression.
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Amyotrophic lateral sclerosis, TARDBP, TDP-43, motor neuron disease, neurodegenerative disorder, human genetics, Amyotrophic Lateral Sclerosis physiopathology, Amyotrophic Lateral Sclerosis diagnosis, Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis complications, motor neuron disease pathology, motor neuron disease metabolism, motor neuron disease complications, atypical motor neuron disease,
