Amir Eldouh

Introduction. Amyotrophic Lateral sclerosis is the most common neurodegenerative disorder of motor neurons in adults, with a median survival of 3 to 5 years after appearance of symptoms, and with no current curative treatment options.¹ There are over 100 ALS-associated genetic mutation, and several mutations leading to mechanistic insight of this complex disease. ² A key pathological hallmark of ALS is the accumulation of misfolded TDP-43. This aggregate is currently thought to cause neuronal damage due to a loss of the native protein’s function and/or by a gain of toxic function exerted through various possible mechanisms.¹ There are no curative treatment for the disease, but disease-modifying therapies have been limited to riluzole.⁷ The pathogenesis of TDP-43 in ALS is an ongoing field of study and is continuing to lead to potential therapies/clinical trials. Methods. Plasmids were used expressing the full length human TDP-43. Dissociated rat cortical or hippocampal neurons were cultured on a feeder layer of astrocytes. All experimental conditions were co-transfected with pCMV-GFP plasmid to visualize cellular morphology. Analysis of the neuronal morphology was performed and image analysis using Maximum Intensity Projections (MIP). Cell death assays, Immunostaining and live imaging were also performed.³ Induction of pluripotent stem cells (ipsc)-derived motor neurons from three ALS patients with different TARDBP mutations. RNA sequencing, live cell imaging of mitochondrial transport and western blots were also done. In vitro experiments were done to demonstrate a direct interaction at the pure protein level. They ran experiments using an antisense oligonucleotide targeting the C4G2 repeats and hypothesized that would reduce the accumulation of TDP-43.⁶ In the clinical trial case, eighteen patients with ALS were randomly assigned into the tamoxifen 40mg/day or placebo group in a double-blinded manner and were also given riluzole twice daily. Participants were then followed up and researchers assessed patient motor/pulmonary functions. Results. Increased TDP-43 expression diminishes dendritic complexity. It was shown that TDP-43 overexpression led to reduced dendritic branching.  HDAC6 inhibition rescues mitochondrial transport defects associated with TDP-43 pathology. A12 h treatment with Tubastatin A, a selective HDAC6 inhibitor, restored the motility of axonal mitochondria in mutant TDP-43 motor neurons compared to controls. It was also established that poly(GR) promotes TDP-43 aggregation through protein-protein interactions. C9ASO treatment, the oligonucleotide antisense proved to reduce the aggregation of TDP-43.Conclusion. These studies prove that the increase in the mechanistic insight of the pathogenesis of TDP-43 in ALS leads to potential therapeutic drugs that could treat the disease.

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