Unveiling the role of p62 at modulating astrocyte reactivity and its implications for ALS/FTD

Amyotrophic lateral sclerosis (ALS) is a fatal late-onset neurodegenerative disease that targets the function and survival of motor neurons in the spinal cord and cortex (1). Notably, ALS shares numerous genetic, clinical, and pathological features with frontotemporal dementia (FTD), leading to their recognition as part of a disease spectrum termed ALS/FTD. Currently, no disease-modifying treatments are available for these devastating illnesses (1).

The accumulation of protein aggregates is a major hallmark of ALS and FTD, suggesting the compromise of protein clearance pathways in the pathogenesis of these diseases (2). One of the ALS/FTD-linked genes encodes sequestosome 1 (SQSTM1/p62), a multi-domain scaffold protein involved in targeting cargo for degradation via autophagy and the ubiquitin-proteasome system. Additionally, p62 serves as a signalling hub for various cellular signal transduction cascades, thereby regulating multiple cellular functions, including the activation of mTORC1 in nutrient sensing, the regulation of inflammation and apoptosis through activation of the nuclear factor kappa-B and the antioxidant response via activation of Keap1-NF-E2-related factor 2 (Nrf2) pathway (3).

Although less extensively investigated, the presence of p62-positive inclusions is not limited to neurons but also extends to astrocytes in the temporal cortex of patients with ALS/FTD (4,5,6,7), as well as astrocytes from FTD cases (8,9) and glial cells in human tauopathies and synucleopathies (10). Despite some evidence, a detailed characterization of the pathology associated with astrocytic p62 in ALS/FTD is currently missing.

In neurodegenerative diseases like ALS and FTD, astrocytes become reactive as part of a conserved physiological response that ultimately result in the gain of new functions and loss or upregulation of homeostatic ones (11). In ALS and FTD, reactive astrocytes contribute to neuron toxicity through non-cell autonomous effects (12). When we modelled...