| Summary: | Recent reports have identified rare, biallelic damaging variants of the <i>AGTPBP1</i> gene that cause a novel and documented human disease known as childhood-onset neurodegeneration with cerebellar atrophy (CONDCA), linking loss of function of the AGTPBP1 protein to human neurodegenerative diseases. CONDCA patients exhibit progressive cognitive decline, ataxia, hypotonia or muscle weakness among other clinical features that may be fatal. Loss of AGTPBP1 in humans recapitulates the neurodegenerative course reported in a well-characterised murine animal model harbouring loss-of-function mutations in the <i>AGTPBP1</i> gene. In particular, in the Purkinje cell degeneration (<i>pcd</i>) mouse model, mutations in <i>AGTPBP1</i> lead to early cerebellar ataxia, which correlates with the massive loss of cerebellar Purkinje cells. In addition, neurodegeneration in the olfactory bulb, retina, thalamus and spinal cord were also reported. In addition to neurodegeneration, <i>pcd</i> mice show behavioural deficits such as cognitive decline. Here, we provide an overview of what is currently known about the structure and functional role of AGTPBP1 and discuss the various alterations in AGTPBP1 that cause neurodegeneration in the <i>pcd</i> mutant mouse and humans with CONDCA. The sequence of neuropathological events that occur in <i>pcd</i> mice and the mechanisms governing these neurodegenerative processes are also reported. Finally, we describe the therapeutic strategies that were applied in <i>pcd</i> mice and focus on the potential usefulness of <i>pcd</i> mice as a promising model for the development of new therapeutic strategies for clinical trials in humans, which may offer potential beneficial options for patients with <i>AGTPBP1</i> mutation-related CONDCA.
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