Mitochondrial dysfunction in ALS

Cozzolino, Mauro; Carrı̀, Maria Teresa

doi:10.1016/j.pneurobio.2011.06.003

Cited by 207 publications

(164 citation statements)

References 192 publications

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“…Similar results have been reported in previous studies where several mtSOD1s were found to accumulate in and on mitochondria to a greater extent than wtSOD1, whereas Cys-6 and Cys-111 mutations reduced SOD1 localization to mitochondria (14,69). Importantly, mtSOD1 accumulation on mitochondria results in mitochondrial dysfunction, which is a feature of FALS (5,6,14,15,70). It is also possible that palmitoylation targets SOD1 to the ER-Golgi pathway, a site for uptake and aggregation of mtSOD1, and could thus contribute to the pathogenic effects of ER stress (7-13) and possibly nonautonomous cell degeneration resulting from the secretion of toxic misfolded mtSOD1 (19,66,71,72).…”

Section: Discussionsupporting

confidence: 89%

Palmitoylation of Superoxide Dismutase 1 (SOD1) Is Increased for Familial Amyotrophic Lateral Sclerosis-linked SOD1 Mutants

Antinone

Ghadge

Lam

et al. 2013

Journal of Biological Chemistry

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Background: Mutations in SOD1 cause familial amyotrophic lateral sclerosis (ALS). Results: SOD1 undergoes palmitoylation in the spinal cord and multiple cell types. Palmitoylation occurs predominantly on immature SOD1 and is increased for ALS-linked SOD1 mutants. Conclusion: Palmitoylation is a reversible post-translational modification of SOD1 cysteine residues. Significance: Palmitoylation could affect SOD1 toxicity by altering its folding, membrane targeting, and/or function.

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Section: Discussionsupporting

confidence: 89%

Palmitoylation of Superoxide Dismutase 1 (SOD1) Is Increased for Familial Amyotrophic Lateral Sclerosis-linked SOD1 Mutants

Antinone

Ghadge

Lam

et al. 2013

Journal of Biological Chemistry

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“…Interestingly, the ontological association between genes affected by a loss of FUS and regulation of mitochondrial function may be relevant, since ALS is associated with changes in mitochondrial structure and activity (Cozzolino and Carri 2012). If a loss of function were caused by FUS mutations in ALS, one would expect to find Ser2 hyperphosphorylation near the TSSs of a large number of genes in affected tissues.…”

Section: Resultsmentioning

confidence: 99%

FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2

Ebmeier²,

et al. 2012

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Mutations in the RNA-binding protein FUS (fused in sarcoma)/TLS have been shown to cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS), but the normal role of FUS is incompletely understood. We found that FUS binds the C-terminal domain (CTD) of RNA polymerase II (RNAP2) and prevents inappropriate hyperphosphorylation of Ser2 in the RNAP2 CTD at thousands of human genes. The loss of FUS leads to RNAP2 accumulation at the transcription start site and a shift in mRNA isoform expression toward early polyadenylation sites. Thus, in addition to its role in alternative RNA splicing, FUS has a general function in orchestrating CTD phosphorylation during RNAP2 transcription.

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“…Furthermore, ALS is marked by mitochondrial dysfunction (61). Recent work has revealed that in the absence of Elp3 in mice, cortical neurogenesis is impaired because of the activation of the unfolded protein response, which is triggered by stress in the endoplasmic reticulum (9).…”

Section: Discussionmentioning

confidence: 99%

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Ohlen

Russell

Brownstein

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Hereditary sensory and autonomic neuropathy type III, or familial dysautonomia [FD; Online Mendelian Inheritance in Man (OMIM) 223900], affects the development and long-term viability of neurons in the peripheral nervous system (PNS) and retina. FD is caused by a point mutation in the gene IKBKAP/ELP1 that results in a tissue-specific reduction of the IKAP/ELP1 protein, a subunit of the Elongator complex. Hallmarks of the disease include vasomotor and cardiovascular instability and diminished pain and temperature sensation caused by reductions in sensory and autonomic neurons. It has been suggested but not demonstrated that mitochondrial function may be abnormal in FD. We previously generated an Ikbkap/Elp1 conditional-knockout mouse model that recapitulates the selective death of sensory (dorsal root ganglia) and autonomic neurons observed in FD. We now show that in these mice neuronal mitochondria have abnormal membrane potentials, produce elevated levels of reactive oxygen species, are fragmented, and do not aggregate normally at axonal branch points. The small hydroxylamine compound BGP-15 improved mitochondrial function, protecting neurons from dying in vitro and in vivo, and promoted cardiac innervation in vivo. Given that impairment of mitochondrial function is a common pathological component of neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's, Parkinson's, and Huntington's diseases, our findings identify a therapeutic approach that may have efficacy in multiple degenerative conditions.T he autonomic nervous system is essential for homeostasis, and its disruption in familial dysautonomia (FD) can have fatal consequences resulting from cardiovascular instability, respiratory dysfunction, and/or sudden death during sleep (1-3). In addition to developmental decreases in the number of sensory and autonomic neurons, FD patients undergo a progressive loss of peripheral neurons and retinal ganglion cells. The latter loss may ultimately lead to blindness (4, 5). More than 98% of FD cases result from a single base substitution (IVS20+6T > C) in the IKBKAP/ELP1 gene (3, 6). This mutation is carried by 1 in 27 to 1 in 32 Ashkenazi Jews (3, 6). The protein encoded by the IKBKAP/ELP1 gene, IKAP/ELP1, is a scaffolding protein for the six-subunit Elongator complex (ELP1-ELP6), which modifies tRNAs during translation (7). Why reduction in the IKAP/ ELP1 protein results in neuronal death is unknown, and we have sought to elucidate the cellular and molecular mechanisms that cause progressive neurodegeneration in FD to help identify treatments that improve neuronal function and viability.Accumulating evidence indicates that cells from FD patients and from mouse models with deletions in the Elongator subunits Ikbkap/Elp1 or Elp3 experience intracellular stress (4,5,(8)(9)(10) resulting from the direct and/or indirect consequences of impaired translation (7, 11). The C terminus of IKAP/ELP1 has been shown to bind c-Jun N-terminal kinase (JNK) and to regulate JNK cytosolic stress signaling (12)....

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Mitochondrial dysfunction in ALS

Cited by 207 publications

References 192 publications

Palmitoylation of Superoxide Dismutase 1 (SOD1) Is Increased for Familial Amyotrophic Lateral Sclerosis-linked SOD1 Mutants

Palmitoylation of Superoxide Dismutase 1 (SOD1) Is Increased for Familial Amyotrophic Lateral Sclerosis-linked SOD1 Mutants

FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

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