Inorganic polyphosphate: from basic research to diagnostic and therapeutic opportunities in ALS/FTD

Abstract

Inorganic polyphosphate (polyP) is a simple, negatively charged biopolymer with chain lengths ranging from just a few to over a thousand ortho-phosphate (Pi) residues. polyP is detected in every cell type across all organisms in nature thus far analyzed. Despite its structural simplicity, polyP has been shown to play important roles in a remarkably broad spectrum of biological processes, including blood coagulation, bone mineralization and inflammation. Furthermore, polyP has been implicated in brain function and the neurodegenerative diseases amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease and Parkinson's disease. In this review, we first address the challenges associated with identifying mammalian polyP metabolizing enzymes, such as Nudt3, and quantifying polyP levels in brain tissue, cultured neural cells and cerebrospinal fluid. Subsequently, we focus on recent studies that unveil how the excessive release of polyP by human and mouse ALS/FTD astrocytes contributes to these devastating diseases by inducing hyperexcitability, leading to motoneuron death. Potential implications of elevated polyP levels in ALS/FTD patients for innovative diagnostic and therapeutic approaches are explored. It is emphasized, however, that caution is required in targeting polyP in the brain due to its diverse physiological functions, serving as an energy source, a chelator for divalent cations and a scaffold for amyloidogenic proteins. Reducing polyP levels, especially in neurons, might thus have adverse effects in brain functioning. Finally, we discuss how activated mast cells and platelets also can significantly contribute to ALS progression, as they can massively release polyP.

Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death

“…Non-cell autonomous toxicity to MNs induced by cultured astrocytes harboring diverse ALScausing gene mutations, including mutations in SOD1, TDP43, and C9ORF72, has also been extensively documented (Dittlau & Bosch, 2023;Garcés et al, 2024;Harten et al, 2021). Our recent study further reveals that excessive inorganic polyphosphate (polyP) released by ALS astrocytes triggers MN death and increases neuronal excitability and Ca 2+ transients (Arredondo et al, 2022;Garcés et al, 2024;Rojas et al, 2023).…”

“…Non-cell autonomous toxicity to MNs induced by cultured astrocytes harboring diverse ALScausing gene mutations, including mutations in SOD1, TDP43, and C9ORF72, has also been extensively documented (Dittlau & Bosch, 2023;Garcés et al, 2024;Harten et al, 2021). Our recent study further reveals that excessive inorganic polyphosphate (polyP) released by ALS astrocytes triggers MN death and increases neuronal excitability and Ca 2+ transients (Arredondo et al, 2022;Garcés et al, 2024;Rojas et al, 2023). Additionally, other studies have also shown that astrocyte-mediated MN degeneration is accompanied by several other pathogenic events, including oxidative stress, induction of a cell death signaling (i.e., phosphorylation of c-Abl), and impaired mitochondrial transport (Birger et al, 2019;Dittlau & Bosch, 2023;Fritz et al, 2013;Haidet-Phillips et al, 2011;Harten et al, 2021;Rojas et al, 2014Rojas et al, , 2015.…”

“…Based on studies in vitro with cultures and in vivo with mouse models, it is widely accepted that MN degeneration in ALS occurs through non-cell-autonomous mechanisms, involving interactions between various local cell types such as astrocytes, microglia, and oligodendrocytes (Ilieva et al, 2009; Maimon & Perlson, 2019). Particularly, there is compelling evidence that ALS astrocytes cause non-cell-autonomous toxicity to MNs (Dittlau & Bosch, 2023; Garcés et al, 2024; Harten et al, 2021). For example, in in vivo studies, the survival of mutSOD1 mice is significantly extended when ALS MNs are surrounded by wild-type (WT) non-neuronal cells (Clement et al, 2003), particularly astrocytes (Lepore et al, 2008).…”

“…Conversely, studies in rodents, either by selectively expressing ALS-linked mutant genes or by transplanting glial progenitors, suggest that fALS astrocytes (Papadeas et al, 2011; Tong et al, 2013), and sALS astrocytes (Qian et al, 2017) can induce certain aspects of MN degeneration, locomotor deficits, and decrease survival. Non-cell autonomous toxicity to MNs induced by cultured astrocytes harboring diverse ALS-causing gene mutations, including mutations in SOD1, TDP43, and C9ORF72, has also been extensively documented (Dittlau & Bosch, 2023; Garcés et al, 2024; Harten et al, 2021). Our recent study further reveals that excessive inorganic polyphosphate (polyP) released by ALS astrocytes triggers MN death and increases neuronal excitability and Ca 2+ transients (Arredondo et al, 2022; Garcés et al, 2024; Rojas et al, 2023).…”