Dr. Van Zundert invites us on an enlightening journey into the intricate world of neurodegenerative diseases, specifically amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These disorders have puzzled researchers for years, especially given the involvement of non-cell-autonomous mechanisms where toxic factors released by astrocytes lead to motorneuron (MN) damage. The heart of this mystery? A compound known as inorganic polyphosphate (polyP).

Delving deep into his research, Dr. Van Zundert unveils a startling discovery. Astrocytes derived from mice and patient-induced pluripotent stem cells (iPSCs) with mutations linked to ALS/FTD (including SOD1, TARDBP, and C9ORF72) exhibit a spike in their intracellular polyP levels. The consequence? Elevated polyP levels in astrocyte-conditioned media (ACM), which, when presented to MNs, has devastating effects.

However, hope looms on the horizon. By degrading or neutralizing polyP, Dr. Van Zundert and his team can successfully stave off ACM-induced MN death. To compound this groundbreaking discovery, postmortem analyses of ALS spinal cords revealed amplified polyP staining signals, and an uptick in polyP concentrations was noted in ALS cerebrospinal fluid (CSF).

This episode unravels the profound implications of these findings. Not only does excessive astrocyte-derived polyP emerge as a critical element in MN degeneration and a potential game-changer in ALS/FTD treatment, but polyP in CSF could revolutionize early detection, positioning itself as a pioneering biomarker for ALS/FTD.

Keyword List:

Neurodegenerative diseases

Amyotrophic lateral sclerosis (ALS)

Frontotemporal dementia (FTD)

Non-cell-autonomous mechanisms

Astrocytes

Motorneurons (MNs)

Inorganic polyphosphate (polyP)

Astrocyte-conditioned media (ACM)

iPSC-derived astrocytes

ALS/FTD-linked mutations

Biomarker

Cerebrospinal fluid (CSF)

Therapeutic target

https://doi.org/10.1016/j.neuron.2022.02.010