Metals in ALS TDP-43 Pathology

Abstract

Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease and similar neurodegenerative disorders take their toll on patients, caregivers and society. A common denominator for these disorders is the accumulation of aggregated proteins in nerve cells, yet the triggers for these aggregation processes are currently unknown. In ALS, protein aggregation has been described for the SOD1, C9orf72, FUS and TDP-43 proteins. The latter is a nuclear protein normally binding to both DNA and RNA, contributing to gene expression and mRNA life cycle regulation. TDP-43 seems to have a specific role in ALS pathogenesis, and ubiquitinated and hyperphosphorylated cytoplasmic inclusions of aggregated TDP-43 are present in nerve cells in almost all sporadic ALS cases. ALS pathology appears to include metal imbalances, and environmental metal exposure is a known risk factor in ALS. However, studies on metal-to-TDP-43 interactions are scarce, even though this protein seems to have the capacity to bind to metals. This review discusses the possible role of metals in TDP-43 aggregation, with respect to ALS pathology.

Studying Peptide-Metal Ion Complex Structures by Solution-State NMR

“…Metal-binding irregularities play a role in diseases such as Alzheimer's [13,14], ALS [15] and neurodegenerative disorders [6], among many others. Nickel and the essential metal, cobalt, are among the metals that can cause allergic reactions in humans [16].…”

“…Paramagnetic probes can be introduced into the molecule by performing two experiments in which the Ca(II) ion is exchanged, respectively by different lanthanides that have dissimilar magnetic susceptibility anisotropy tensors, such as Tb(III) or Tm(III): Internuclear vectors referenced to each lanthanide provide additional information regarding internal orientation relative to the paramagnetic probe [109,110]. The relative dynamic motion of the bound and apo structures of calmodulin can be measured by 1 H- 15 N transverse relaxation optimized spectroscopy-heteronuclear single quantum coherence (TROSY-HSQC) experiments [111].…”

“…Destabilization and misfolding caused by manganese-binding in prion disease [149] was studied with a 30-amino acid peptide comprising three repeats of a decapeptide repeat in the C-terminal region of the calcium protein, Cap43, that was probed using 1D 1 H-NMR to follow line-broadening upon binding and elucidate the role of divalent ions in the pathogenesis of prion disease [150]. Mn(II) ion binding to a peptide derived from amyloid beta, Aβ (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), was also studied by measuring line-broadening upon binding by 1D 1 H-NMR [151].…”

“…A model of the structure of a complex of Co(II) and a fragment of amyloid beta protein, Aβ (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), was determined by canonical methodology on a sample with a 1:0.01 molar ratio of peptide-to-cobalt. The intensity of the signals were measured as a function of titration and signals with reduced intensity were considered to be proximate to the cobalt ion and served as the cobalt binding center [151].…”

Cognitive and Physical Intervention in Metals’ Dysfunction and Neurodegeneration

“…Many facts and mechanisms may be involved in this process, as epidemiological studies suggest a relationship between environmental exposure to metals and the risk of PD, as it has been observed that disorders with brain-metal accumulation may manifest with parkinsonism; in animal studies, the effects of chelation treatment were detected, and measurements of metal concentrations and metal regulatory protein expression in cerebrospinal fluid and post-mortem brain-tissue samples [32]. ALS pathology also appears to include metal imbalances, and a known risk factor for ALS can be environmental-metal exposure [33]. It has been proven that administration of a Cu-chelating agent (ammonium tetrathiomolybdate) enhanced survival and slowed ALS progression [34].There is accumulating evidence that exercise can enhance brain function and attenuate neurodegeneration in such mechanisms as improving neuroplasticity by altering the synaptic structure and function in many brain regions.…”