Concise review: The Cellular Conspiracy of ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is incurable and devastating. A dearth of therapies has galvanized experimental focus onto the cellular and molecular mechanisms that both initiate and subsequently drive motor neuron (MN) degeneration. A traditional view of ALS pathogenesis posits that disease-specific injury to a subtype of neurons is mechanistically cell-autonomous. This "neuron-centric" view has biased past research efforts. However, a wealth of accumulating evidence now strongly implicates non-neuronal cells as being major determinants of ALS. Although animal models have proven invaluable in basic neuroscience research, a growing number of studies confirm fundamental interspecies differences between popular model organisms and the human condition. This may in part explain the failure of therapeutic translation from rodent pre-clinical models. It follows that integration of a human experimental model utilizing patient-specific induced pluripotent stem cells (hiPSCs) may be necessary to capture the complexity of human neurodegeneration with fidelity. Integration of enriched human neuronal and glial experimental platforms into the existing repertoire of preclinical models might prove transformational for clinical trial outcomes in ALS. Such reductionist and integrated cross-modal approaches allow systematic elucidation of cell-autonomous and non-cell-autonomous mechanisms of disease, which may then provide novel cellular targets for therapeutic intervention. This article is protected by copyright. All rights reserved.

"Intricate and self-perpetuating cellular interplay underlies amyotrophic lateral sclerosis (ALS). Disease stage is a key determinant of cell type-specific molecular mechanisms".

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