Astrocytes and microglial cells are the most frequently co-occurring cell types with ALS and HD in the rare diseases-related documents of the CAS Content Collection, while MG exhibits high co-occurrence with T-cells and B-cells (Figure ). While ALS is traditionally considered a motor neuron disease and HDa neuronal disorder caused by mutant huntingtin protein (mHTT), emerging evidence suggests that non-neuronal cells, particularly astrocytes, microglia, and other types of neuroglia, play crucial roles in ALS and HD pathogenesis. Astrocytes, the most abundant glial cells in the central nervous system, are implicated in ALS and HD through various mechanisms. Reactive astrocytes can secrete toxic molecules, such as pro-inflammatory cytokines and ROS, contributing to neuronal damage and death. Dysfunctional astrocytes also fail to provide adequate support to neurons, impairing their survival and function. Furthermore, mutations in genes like SOD1 and C9orf72, associated with familial ALS cases, have been shown to induce astrocyte dysfunction, exacerbating disease progression. Reactive astrocytes in HD exhibit altered morphology and dysregulated function, including impaired glutamate uptake and disrupted calcium signaling. Dysfunction of astrocytes contributes to excitotoxicity, oxidative stress, and neuronal dysfunction in HD. Additionally, astrocytes expressing mHTT can release toxic factors, exacerbating neuronal damage and disease progression. Microglia, the resident immune cells of the central nervous system, play dual roles in ALS and HD pathology. While initially recruited to sites of neuronal injury to clear cellular debris and promote tissue repair, microglia can become chronically activated and contribute to neuroinflammation and neurotoxicity. Dysregulated microglial responses, characterized by the release of pro-inflammatory cytokines and neurotoxic factors, have been implicated in motor neuron degeneration. Modulating microglial activation and promoting their neuroprotective functions represent potential therapeutic strategies for ALS and HD.