Molecular Mechanisms in Amyotrophic Lateral Sclerosis: The Role of Angiogenin, a Secreted RNase

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease caused by the loss of motoneurons. The precise molecular and cellular basis for neuronal death is not yet well established, but the contemporary view is that it is a culmination of multiple aberrant biological processes. Among the proposed mechanisms of motoneuron degeneration, alterations in the homeostasis of RNA binding proteins (RBP) and the consequent changes in RNA metabolism have received attention recently.The ribonuclease, angiogenin was one of the first RBPs associated with familial and sporadic ALS. It is enriched in motoneurons under physiological conditions, and is required for motoneuron survival under stress conditions. Furthermore, delivery of angiogenin protects cultured motoneurons against stress-induced injury, and significantly increases the survival of motoneurons in SODG93A mice. In this overview on the role of angiogenin in RNA metabolism and in the control of motoneuron survival, we discuss potential pathogenic mechanisms of angiogenin dysfunction relevant to ALS and other neurodegenerative disorders. We also discuss recent evidence demonstrating that angiogenin secreted from stressed motoneurons may alter RNA metabolism in astrocytes

Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD-ALS spectrum disorders

Aggregation of misfolded TAR DNA-binding protein 43 (TDP-43) is a striking hallmark of neurodegenerative processes that are observed in several neurological disorders, and in particular in most patients diagnosed with frontotemporal lobar degeneration (FTLD) or amyotrophic lateral sclerosis (ALS). A direct causal link with TDP-43 brain proteinopathy was provided by the identification of pathogenic mutations in TARDBP, the gene encoding TDP-43, in ALS families. However, TDP-43 proteinopathy has also been observed in carriers of mutations in several other genes associated with both ALS and FTLD demonstrating a key role for TDP-43 in neurodegeneration. To date, and despite substantial research into the biology of TDP-43, its functioning in normal brain and in neurodegeneration processes remains largely elusive. Nonetheless, breakthroughs using cellular and animal models have provided valuable insights into ALS and FTLD pathogenesis. Accumulating evidence has redirected the research focus towards a major role for impaired RNA metabolism and protein homeostasis. At the same time, the concept that toxic TDP-43 protein aggregates promote neurodegeneration is losing its credibility. This review aims at highlighting and discussing the current knowledge on TDP-43 driven pathomechanisms leading to neurodegeneration as observed in TDP-43 proteinopathies. Based on the complexity of the associated neurological diseases, a clear understanding of the essential pathological modifications will be crucial for further therapeutic interventions