Early decrease of mitochondrial DNA repair enzymes in spinal motor neurons of presymptomatic transgenic mice carrying a mutant SOD1 gene

Amyotrophic lateral sclerosis (ALS) is a devastating, motor neuron degenerative disease without any cure. About 95% of the ALS patients feature abnormalities in the RNA/DNA-binding protein, TDP-43, involving its nucleo-cytoplasmic mislocalization in spinal motor neurons. How TDP-43 pathology triggers neuronal apoptosis remains unclear. In a recent study, we reported for the first time that TDP-43 participates in the DNA damage response (DDR) in neurons, and its nuclear clearance in spinal motor neurons caused DNA double-strand break (DSB) repair defects in ALS. We documented that TDP-43 was a key component of the non-homologous end joining (NHEJ) pathway of DSB repair, which is likely the major pathway for repair of DSBs in post-mitotic neurons. We have also uncovered molecular insights into the role of TDP-43 in DSB repair and showed that TDP-43 acts as a scaffold in recruiting the XRCC4/DNA Ligase 4 complex at DSB damage sites and thus regulates a critical rate-limiting function in DSB repair. Significant DSB accumulation in the genomes of TDP-43-depleted, human neural stem cell-derived motor neurons as well as in ALS patient spinal cords with TDP-43 pathology, strongly supported a TDP-43 involvement in genome maintenance and toxicity-induced genome repair defects in ALS. In this commentary, we highlight our findings that have uncovered a link between TDP-43 pathology and impaired DNA repair and suggest potential possibilities for DNA repair-targeted therapies for TDP-43-ALS.

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Restricted expression of mutant SOD1 in spinal motor neurons and interneurons induces motor neuron pathology

Neurobiology of Disease ◽

10.1016/j.nbd.2007.10.004 ◽

2008 ◽

Vol 29 (3) ◽

pp. 400-408 ◽

Cited By ~ 56

Author(s):

Lijun Wang ◽

Kamal Sharma ◽

Han-Xiang Deng ◽

Teepu Siddique ◽

Gabriella Grisotti ◽

...

Keyword(s):

Motor Neuron ◽

Motor Neurons ◽

Mutant Sod1 ◽

Spinal Motor Neurons ◽

Spinal Motor

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Antagonistic Roles of Neurofilament Subunits NF-H and NF-M Against NF-L in Shaping Dendritic Arborization in Spinal Motor Neurons

The Journal of Cell Biology ◽

10.1083/jcb.140.5.1167 ◽

1998 ◽

Vol 140 (5) ◽

pp. 1167-1176 ◽

Cited By ~ 35

Author(s):

Jiming Kong ◽

Vivian W.-Y. Tung ◽

John Aghajanian ◽

Zuoshang Xu

Keyword(s):

Transgenic Mice ◽

Motor Neurons ◽

Cellular Mechanism ◽

Dendritic Arborization ◽

Neuronal Function ◽

Dendritic Trees ◽

Cytoskeletal Organization ◽

Spinal Motor Neurons ◽

Spinal Motor ◽

Lower Ratio

Dendrites play important roles in neuronal function. However, the cellular mechanism for the growth and maintenance of dendritic arborization is unclear. Neurofilaments (NFs), a major component of the neuronal cytoskeleton, are composed of three polypeptide subunits, NF-H, NF-M, and NF-L, and are abundant in large dendritic trees. By overexpressing each of the three NF subunits in transgenic mice, we altered subunit composition and found that increasing NF-H and/or NF-M inhibited dendritic arborization, whereas increasing NF-L alleviated this inhibition. Examination of cytoskeletal organization revealed that increasing NF-H and/or NF-M caused NF aggregation and dissociation of the NF network from the microtubule (MT) network. Increasing NF-H or NF-H together with NF-M further reduced NFs from dendrites. However, these changes were reversed by elevating the level of NF-L with either NF-H or NF-M. Thus, NF-L antagonizes NF-H and NF-M in organizing the NF network and maintaining a lower ratio of NF-H and NF-M to NF-L is critical for the growth of complex dendritic trees in motor neurons.

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